Compounds

ABSTRACT

Piperidine derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man.

This invention relates to novel compounds, compositions containing themand their use as antibacterials.

WO99/37635, WO00/21948, WO00/21952, WO00/43383, WO00/8748, WO01/07432,WO01/07433, WO02/08224, WO02/24684, WO02/50040, WO02/56882, WO02/96907,PCT/EP02/05708, WO03010138, WO01/25227, WO0240474 and WO0207572 disclosecyclohexane, piperidine and piperazine derivatives having antibacterialactivity.

This invention provides a compound of formula (1) or a pharmaceuticallyacceptable derivative thereof:

wherein:

-   R^(A) is an optionally substituted bicyclic carbocyclic or    heterocyclic ring system of structure:    containing 0-3 heteroatoms in each ring in which:    -   at least one of rings (x) and (y) is aromatic;    -   one of Z⁴ and Z⁵ is C or N and the other is C;    -   Z³ is N, NR¹³, O, S(O)_(x), CO, CR¹ or CR¹R^(1a);    -   Z¹ and Z² are independently a 2 or 3 atom linker group each atom        of which is independently selected from N, NR¹³, O, S(O)_(x),        CO, CR¹ and CR¹R^(1a); such that each ring is independently        substituted with 0-3 groups R¹ and/or R^(1a);-   one of Z¹, Z², Z³, Z⁴ and Z⁵ is N, one is CR^(1a) and the remainder    are CH, or one of Z¹, Z², Z³, Z⁴ and Z⁵ is CR^(1a) and the remainder    are CH;-   R¹ and R^(1a) are independently hydrogen; hydroxy; (C₁₋₆)alkoxy    optionally substituted by (C₁₋₆)alkoxy, amino, piperidyl, guanidino    or amidino any of which is optionally N-substituted by one or two    (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups, CONH₂, hydroxy,    (C₁₋₆)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio,    aryloxy, acylthio, acyloxy or (C₁₋₆)alkylsulphonyloxy;    (C₁₋₆)alkoxy-substituted(C₁₋₆)alkyl; hydroxy (C₁₋₆)alkyl; halogen;    (C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluoromethyl; trifluoromethoxy;    cyano; carboxy; nitro; azido; acyl; acyloxy; acylthio;    (C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide; arylsulphonyl;    arylsulphoxide or an amino, piperidyl, guanidino or amidino group    optionally N-substituted by one or two (C₁₋₆)alkyl, acyl or    (C₁₋₆)alkylsulphonyl groups, or when Z³ and the adjacent atom are    CR¹ and CR^(1a) , R¹ and R^(1a) may together represent    (C₁₋₂)alkylenedioxy;    provided that R¹ and R^(1a), on the same carbon atom are not both    optionally substituted hydroxy or amino;    provided that-   (i) when R^(A) is optionally substituted quinolin-4-yl:    -   it is unsubstituted in the 6-position; or    -   it is substituted by at least one hydroxy (C₁₋₆)alkyl, cyano or        carboxy group at the 2-, 5-, 6-, 7- or 8-position; or    -   it is substituted by at least one trifluoromethoxy group; or    -   R¹ and R^(1a) together represent (C₁₋₂)alkylenedioxy;-   (ii) when R^(A) is optionally substituted quinazolin-4-yl,    cinnolin-4-yl, 1,5-naphthyridin-4-yl, 1,7-naphthyridin-4-yl or    1,8-naphthyridin-4-yl:    -   it is substituted by at least one hydroxy (C₁₋₆)alkyl, cyano or        carboxy group at the 2-, 5-, 6-, 7- or 8-position as available;        or    -   it is substituted by at least one trifluoromethoxy group; or    -   R¹ and R^(1a) together represent (C₁₋₂)alkylenedioxy;-   R² is hydrogen, or (C₁₋₄)alkyl or (C₂₋₄)alkenyl optionally    substituted with 1 to 3 groups selected from:-   amino optionally substituted by one or two (C₁₋₄)alkyl groups;    carboxy; (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl;    (C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; aminocarbonyl    wherein the amino group is optionally substituted by hydroxy,    (C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl(C₁₋₄)alkyl,    (C₂₋₄)alkenyl, (C₁₋₄)alkylsulphonyl, trifluoromethylsulphonyl,    (C₂₋₄)alkenylsulphonyl, (C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl,    (C₂₋₄)alkenyloxycarbonyl or (C₂₋₄)alkenylcarbonyl; cyano;    tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R¹⁰;    3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;    tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally    substituted by R¹⁰; 5-oxo-1,2,4-oxadiazol-3-yl; halogen;    (C₁₋₄)alkylthio; trifluoromethyl; hydroxy optionally substituted by    (C₁₋₄)alkyl, (C₂₋₄)alkenyl, (C₁₋₄)alkoxycarbonyl,    (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,    (C₂₋₄)alkenylcarbonyl; oxo; (C₁₋₄)alkylsulphonyl;    (C₂₋₄)alkenylsulphonyl; or (C₁₋₄)aminosulphonyl wherein the amino    group is optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl;-   R³ is hydrogen; or-   R³ is in the 2-, 3- or 4-position and is:-   trifluoromethyl; carboxy; (C₁₋₆)alkoxycarbonyl;    (C₂₋₆)alkenyloxycarbonyl; aminocarbonyl wherein the amino group is    optionally substituted by hydroxy, (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,    aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl,    trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl,    (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl    or (C₂₋₆)alkenylcarbonyl and optionally further substituted by    (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or    (C₂₋₆)alkenyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally    substituted by R¹⁰; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl;    2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl;    1,2,4-triazol-5-yl optionally substituted by R¹⁰; or    5-oxo-1,2,4-oxadiazol-3-yl; or-   (C₁₋₄)alkyl or ethenyl optionally substituted with any of the    substituents listed above for R³ and/or 0 to 2 groups R¹²    independently selected from:    -   halogen; (C₁₋₆)alkylthio; trifluoromethyl; (C₁₋₆)alkoxycarbonyl;        (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;        (C₂₋₆)alkenylcarbonyl; hydroxy optionally substituted by        (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,        (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,        (C₂₋₆)alkenylcarbonyl or aminocarbonyl wherein the amino group        is optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,        (C₁₋₆)alkylcarbonyl or (C₂₋₆)alkenylcarbonyl; amino optionally        mono- or disubstituted by (C₁₋₆)alkoxycarbonyl,        (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,        (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,        (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl or aminocarbonyl        wherein the amino group is optionally substituted by (C₁₋₆)alkyl        or (C₂₋₆)alkenyl; aminocarbonyl wherein the amino group is        optionally substituted by (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,        aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkoxycarbonyl,        (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or        (C₂₋₆)alkenylcarbonyl and optionally further substituted by        (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or        (C₂₋₆)alkenyl; oxo; (C₁₋₆)alkylsulphonyl;        (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonyl wherein the        amino group is optionally substituted by (C₁₋₆)alkyl or        (C₂₋₆)alkenyl; or-   R³ is in the 2-position and is oxo; or-   R³ is in the 3-position and is fluorine, amino optionally    substituted by a group selected from hydroxy, (C₁₋₆)alkylsulphonyl,    trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl,    (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkoxycarbonyl,    (C₂₋₆)alkenyloxycarbonyl, (C₁₋₆)alkyl and (C₂₋₆)alkenyl, wherein a    (C₁₋₆)alkyl or (C₂₋₆)alkenyl moiety may be optionally substituted    with up to 2 groups R¹², or hydroxy optionally substituted as    described above for R¹² hydroxy;-   in addition when R³ is disubstituted with a hydroxy or amino    containing substituent and carboxy containing substituent these may    together form a cyclic ester or amide linkage, respectively;-   R⁴ is a group -U-R⁵ where-   U is selected from CO, SO₂ and CH₂ and-   R⁵ is an optionally substituted bicyclic carbocyclic or heterocyclic    ring system (A):    containing up to four heteroatoms in each ring in which    -   at least one of rings (a)and (b) is aromatic;    -   X¹ is C or N when part of an aromatic ring, or CR¹⁴ when part of        a non-aromatic ring;    -   X² is N, NR¹³, O, S(O)_(x), CO or CR¹⁴ when part of an aromatic        or non-aromatic ring or may in addition be CR¹⁴R¹⁵ when part of        a non aromatic ring;    -   X³ and X⁵ are independently N or C;    -   Y¹ is a 0 to 4 atom linker group each atom of which is        independently selected from N, NR¹³, O, S(O)_(x), CO and CR¹⁴        when part of an aromatic or non-aromatic ring or may        additionally be CR¹⁴R¹⁵ when part of a non aromatic ring;    -   Y² is a 2 to 6 atom linker group, each atom of Y² being        independently selected from N, NR¹³, O, S(O)_(x), CO, CR¹⁴ when        part of an aromatic or non-aromatic ring or may additionally be        CR¹⁴R¹⁵ when part of a non aromatic ring;    -   each of R¹⁴ and R¹⁵ is independently selected from: H;        (C₁₋₄)alkylthio; halo; carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy;        halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl;        (C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;        (C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl;        (C₁₋₄)alkylcarbonyloxy; (C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl;        hydroxy; hydroxy(C₁₋₄)alkyl; mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy;        nitro; cyano; carboxy; amino or aminocarbonyl optionally        substituted as for corresponding substituents in R³;        (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonyl        wherein the amino group is optionally mono- or di-substituted by        (C₁₋₄)alkyl or (C₂₋₄)alkenyl; aryl; aryl(C₁₋₄)alkyl;        aryl(C₁₋₄)alkoxy or    -   R¹⁴ and R¹⁵ may together represent oxo;    -   each R¹³ is independently H; trifluoromethyl; (C₁₋₄)alkyl        optionally substituted by hydroxy, (C₁₋₆)alkoxy,        (C₁₋₆)alkylthio, halo or trifluoromethyl; (C₂₋₄)alkenyl; aryl;        aryl (C₁₋₄)alkyl; arylcarbonyl; heteroarylcarbonyl;        (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; formyl;        (C₁₋₆)alkylsulphonyl; or aminocarbonyl wherein the amino group        is optionally substituted by (C₁₋₄)alkoxycarbonyl,        (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,        (C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or (C₂₋₄)alkenyl and        optionally further substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl;-   each x is independently 0, 1 or 2-   n is 0 and AB is NR¹¹CO, CO—CR⁸R⁹, CR⁶R⁷—CO, NHR¹¹SO₂, CR⁶R⁷—SO₂ or    CR⁶R⁷ 13 CR⁸R⁹, provided that R⁸ and R⁹ are not optionally    substituted hydroxy or amino and R⁶ and R⁸ do not represent a bond:-   or n is 1 and AB is NR¹¹CO, CO—CR⁸R⁹, CR⁶R⁷—CO, NR¹¹SO₂, CONR¹¹,    CR⁶R⁷—CR⁸R⁹, O—CR⁸R⁹ or NR¹¹—CR⁸R⁹;-   provided that R⁶ and R⁷, and R⁸ and R⁹ are not both optionally    substituted hydroxy or amino;-   and wherein:-   each of R⁶, R⁷, R⁸ and R⁹ is independently selected from: H;    (C₁₋₆)alkoxy; (C₁₋₆)alkylthio; halo; trifluoromethyl; azido;    (C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl;    (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;    (C₂₋₆)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally    substituted as for corresponding substituents in R³;    (C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or    (C₁₋₆)aminosulphonyl wherein the amino group is optionally    substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl;-   or R⁶ and R⁸ together represent a bond and R⁷ and R⁹ are as above    defined;-   R¹⁰ is selected from (C₁₋₄)alkyl; (C₂₋₄)alkenyl and aryl any of    which may be optionally substituted by a group R¹² as defined above;    carboxy; aminocarbonyl wherein the amino group is optionally    substituted by hydroxy, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,    (C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl,    (C₂₋₆)alkenylsulphonyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,    (C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyl and optionally    further substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; and-   R¹¹ is hydrogen; trifluoromethyl, (C₁₋₆)alkyl; (C₂₋₆)alkenyl;    (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; or aminocarbonyl wherein    the amino group is optionally substituted by (C₁₋₆)alkoxycarbonyl,    (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,    (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl or (C₂₋₆)alkenyl and optionally    further substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl;-   or where one of R³ and R⁶, R⁷, R⁸ or R⁹ contains a carboxy group and    the other contains a hydroxy or amino group they may together form a    cyclic ester or amide linkage.

This invention also provides a method of treatment of bacterialinfections in mammals, particularly in man, which method comprises theadministration to a mammal in need of such treatment an effective amountof a compound of formula (I), or a pharmaceutically acceptablederivative thereof.

The invention also provides the use of a compound of formula (I), or apharmaceutically acceptable derivative thereof, in the manufacture of amedicament for use in the treatment of bacterial infections in mammals.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable derivativethereof, and a pharmaceutically acceptable carrier.

In one aspect R^(A) is not indole or benzofuran.

Preferably Z² is three atoms long.

Preferably Z⁴ and Z⁵ are both carbon.

Preferably Z¹ is three atoms long with carbon joined to Z³ and with R¹on the carbon atom joined to Z³.

In one preferred aspect, R^(A) is aromatic and ring (y) is fusedbenzene. Preferably (x) is 6-membered containing one or two nitrogenatoms, the remainder being carbon. Most preferably Z³ is nitrogen andthe remainder are carbon or Z¹ is ═CH—CH═N— (N attached to Z⁵).

In another preferred aspect, ring (y) is fused pyridin-4-yl (Z² is threeatoms long, the atom attached to Z⁵ in Z² is nitrogen and the remainderand Z⁴ and Z⁵ are carbon), Z¹ is two or three atoms long and Z³ is aheteroatom such as O or S.

Suitable examples of rings R^(A) include optionally substitutedisoquinolin-5-yl, quinolin-8-yl, thieno[3,2-b]pyridin-7-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinoxalin-5-yl,isoquinolin-8-yl, [1,6]-naphthyridin-4-yl,1,2,3,4-tetrahydroquinoxalin-5-yl and 1,2-dihydroisoquinoline-8-yl. Mostpreferably R^(A) is optionally 2-substituted-quinolin-8-yl or optionally3-substituted-quinoxalin-5-yl.

R¹³ in rings (x) and (y) is preferably H or (C₁₋₆)alkyl.

When R¹ or R^(1a) is substituted alkoxy it is preferably (C₂₋₆)alkoxysubstituted by optionally N-substituted amino, or (C₁₋₆)alkoxysubstituted by piperidyl. Suitable examples of R¹ and R^(1a) alkoxyinclude methoxy, trifluoromethoxy, n-propyloxy, iso-butyloxy,aminoethyloxy, aminopropyloxy, aminobutyloxy, aminopentyloxy,guanidinopropyloxy, piperidin-4-ylmethyloxy or2-aminocarbonylprop-2-oxy.

Preferably R¹ and R^(1a) are independently hydrogen, (C₁₋₄)alkoxy,(C₁₋₄)alkylthio, (C₁₋₄)alkyl, amino(C₃₋₅)alkyloxy, nitro, cyano,carboxy, hydroxymethyl or halogen; more preferably hydrogen, methoxy,methyl, cyano, halogen or amino(C₃₋₅)alkyloxy. Ring R^(A) is preferablysubstituted by one group R¹. Most preferably R¹ is H, methoxy, methyl,cyano or halogen and R^(1a) is H. Halogen is preferably chloro orfluoro.

Preferably n is 0.

R² is preferably hydrogen; (C₁₋₄)alkyl substituted with carboxy,optionally substituted hydroxy, optionally substituted aminocarbonyl,optionally substituted amino or (C₁₋₄)alkoxycarbonyl; or (C₂₋₄)alkenylsubstituted with (C₁₋₄)alkoxycarbonyl or carboxy. More preferred groupsfor R² are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylalkyl and carboxyalkyl, mostpreferably hydrogen.

Preferred examples of R³ include hydrogen; optionally substitutedhydroxy; optionally substituted amino; halogen; (C₁₋₄)alkoxycarbonyl;(C₁₋₄) alkyl; ethenyl; optionally substituted 1-hydroxy-(C₁₋₄) alkyl;optionally substituted aminocarbonyl; carboxy(C₁₋₄)alkyl; optionallysubstituted aminocarbonyl(C₁₋₄)alkyl; cyano(C₁₋₄)alkyl; optionallysubstituted 2-oxo-oxazolidinyl and optionally substituted2-oxo-oxazolidinyl(C₁₋₄alkyl). More preferred R³ groups are hydrogen;CONH₂; 1-hydroxyalkyl e.g. CH₂OH, CH(OH)CH₂CN; CH₂CO₂H; CH₂CONH₂;CONHCH₂CONH₂; 1,2-dihydroxyalkyl e.g. CH(OH)CH₂OH; CH₂CN;2-oxo-oxazolidin-5-yl, 2-oxo-oxazolidin-5-yl(C₁₋₄alkyl); optionallysubstituted hydroxy; optionally substituted amino; and halogen, inparticular fluoro. Most preferably R³ is hydrogen, hydroxy or fluoro.

R³ is preferably in the 3- or 4-position.

When R³ is in the 3-position, preferably it is trans to (NR²)R⁴ and hasR stereochemistry or is cis to NR²R⁴ and has S stereochemistry.

When R³ and R⁶, R⁷, R⁸ or R⁹ together form a cyclic ester or amidelinkage, it is preferred that the resulting ring is 5-7 membered. It isfurther preferred that the group A or B which does not form the ester oramide linkage is CH₂.

Preferably n=0.

In one aspect, CR⁶R⁷ is CH₂, CHOH, CH(NH₂), C(Me)(OH) or CH(Me) andCR⁸R⁹ is CH₂.

When A is CH(OH) the R-stereochemistry is preferred.

Preferably A is NH, NCH₃, CH₂, CHOH, CH(NH₂), C(Me)(OH) or CH(Me).

Preferably B is CH₂ or CO.

Preferably A-B is CH₂—CH₂, CHOH—CH₂, NR¹¹—CH₂ or NR¹¹—CO.

Particularly preferred are those compounds where n=0, A and B are bothCH₂, A is NH and B is CO, or A is CHOH and B is CH₂, when morepreferably A is the R-isomer of CHOH.

Preferably R¹¹ is hydrogen or (C₁₋₄)alkyl e.g. methyl, more preferablyhydrogen.

U is most preferably CH₂.

Preferably R⁵ is an aromatic heterocyclic ring (A) having 8-11 ringatoms including 2-4 heteroatoms of which at least one is N or NR¹³ inwhich preferably Y² contains 2-3 heteroatoms, one of which is S and 1-2are N, with one N bonded to X³.

Alternatively and preferably the heterocyclic ring (A) has ring (a)aromatic selected from optionally substituted benzo and pyrido and ring(b) non aromatic and Y² has 3-5 atoms, more preferably 4 atoms,including a heteroatom bonded to X⁵ selected from O, S or NR³, where R¹³is other than hydrogen, and NHCO bonded via N to X³, or O bonded to X³.The ring (a) preferably contains aromatic nitrogen, and more preferablyring (a) is pyridine. Examples of rings (A) include optionallysubstituted:

(a) and (b) Aromatic

1H-pyrrolo[2,3-b]-pyridin-2-yl, 1H-pyrrolo[3,2-b]-pyridin-2-yl,3H-imidazo[4,5-b]-pyrid-2-yl, 3H-quinazolin-4-one-2-yl,benzimidazol-2-yl, benzo[1,2,3]-thiadiazol-5-yl,benzo[1,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl,benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl,imidazo[1,2-a]pyridin-2-yl, imidazo-[1,2-a]-pyrimidin-2-yl, indol-2-yl,indol-6-yl, isoquinolin-3-yl, [1,8]-naphthyridine-3-yl,oxazolo[4,5-b]-pyridin-2-yl, quinolin-2-yl, quinolin-3-yl,quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl, 1,3-dioxo-isoindol-2-yl,benzimidazol-2-yl, benzothiophen-2-yl, 1H-benzotriazol-5-yl,1H-indol-5-yl, 3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thione-6-yl,3H-benzothiazol-2-one-5-yl, 3H-quinazolin-4-one-2-yl,3H-quinazolin-4-one-6-yl, 4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl,benzo[1,2,3]thiadiazol-6-yl, benzo[1,2,5]thiadiazol-5-yl,benzo[1,4]oxazin-2-one-3-yl, benzothiazol-5-yl, benzothiazol-6-yl,cinnolin-3-yl, imidazo[1,2-a]pyridazin-2-yl,imidazo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyrazin-2-yl,pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyrimidin-6-yl,pyrazolo[5,1-c][1,2,4]triazin-3-yl, pyrido[1,2-a]pyrimdin-4-one-2-yl,pyrido[1,2-a]pyrimidin-4-one-3-yl, quinazolin-2-yl, quinoxalin-6-yl,thiazolo[3,2-a]pyrimidin-5-one-7-yl, thiazolo[5,4-b]pyridin-2-yl,thieno[3,2-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-6-yl,4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl,1-oxo-1,2-dihydro-isoquinolin-3-yl, thiazolo[4,5-b]pyridin-5-yl,[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-1-one-3-yl

(a) Is Non Aromatic

(2S)-2,3-dihydro-1H-indol-2-yl, (2S)-2,3-dihydro-benzo[1,4]dioxine-2-yl,3-(R,S)-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl,3-(R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,3-(S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,2,3-dihydro-benzo[1,4]dioxan-2-yl,3-substituted-3H-quinazolin-4-one-2-yl,

(b) Is Non Aromatic

1,1,3-trioxo-1,2,3,4-tetrahydrol l⁶-benzo[1,4]thiazin-6-yl,benzo[1,3]dioxol-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl,2-oxo-2,3-dihydro-benzooxazol-6-yl,3-substituted-3H-benzooxazol-2-one-6-yl,3-substituted-3H-benzooxazole-2-thione-6-yl,3-substituted-3H-benzothiazol-2-one-6-yl, 4H-benzo[1,4]oxazin-3-one-6-yl(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl),4H-benzo[1,4]thiazin-3-one-6-yl(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl),4H-benzo[1,4]oxazin-3-one-7-yl,4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-yl,5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl,benzo[1,3]dioxol-5-yl, 1H-pyrido[2,3-b][1,4]thiazin-2-one-7-yl(2-oxo-2,3-dihydro-1H-pyrido[2,3-b]thiazin-7-yl),2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,2-oxo-2,3-dihydro-1H-pyrido[3,4-b]thiazin-7-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl,3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,3,4-dihydro-1H-quinolin-2-one-7-yl,3,4-dihydro-1H-quinoxalin-2-one-7-yl,6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one-2-yl,5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl,2-oxo-3,4-dihydro-1H-[1,8]naphthyridin-6-yl,6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-yl,2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-yl,2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl.

R¹³ is preferably H if in ring (a) or in addition (C₁₋₄)alkyl such asmethyl or isopropyl when in ring (b). More preferably, in ring (b) R¹³is H when NR¹³ is bonded to X³ and (C₁₋₄)alkyl when NR¹³ is bonded toX⁵.

R¹⁴ and R¹⁵ are preferably independently selected from hydrogen, halo,hydroxy, (C₁₋₄) alkyl, (C₁₋₄)alkoxy, trifluoromethoxy, nitro, cyano,aryl(C₁₋₄)alkoxy and (C₁₋₄)alkylsulphonyl. More preferably R¹⁵ ishydrogen.

More preferably each R¹⁴ is selected from hydrogen, chloro, fluoro,hydroxy, methyl, methoxy, trifluoromethoxy, benzyloxy, nitro, cyano andmethylsulphonyl. Most preferably R¹⁴ is selected from hydrogen, fluorineor nitro.

Most preferably R¹⁴ and R¹⁵ are each H.

Most preferred groups R⁵ include:

-   [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl-   1H-Pyrrolo[2,3-b]pyridin-2-yl-   2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl-   2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl-   2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl-   2,3-dihydro-benzo[1,4]dioxin-6-yl-   2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl-   2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl-   3,4-dihydro-2H-benzo[1,4]oxazin-6-yl-   3-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl-   3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl-   3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl    (4H-benzo[1,4]thiazin-3-one-6-yl)-   4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl-   6-nitro-benzo[1,3]dioxol-5-yl-   7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl-   8-Hydroxy-1-oxo-1,2-dihydro-isoquinolin-3-yl-   8-hydroxyquinolin-2-yl-   benzo[1,2,3]thiadiazol-5-yl-   benzo[1,2,5]thiadiazol-5-yl-   benzothiazol-5-yl-   thiazolo-[5,4-b]pyridin-6-yl-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl    especially-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl.

When used herein, the term “alkyl” includes groups having straight andbranched chains, for instance, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl and hexyl. The term‘alkenyl’ should be interpreted accordingly.

Halo or halogen includes fluoro, chloro, bromo and iodo.

Haloalkyl moieties include 1-3 halogen atoms.

Unless otherwise defined, the term “heterocyclic” as used hereinincludes optionally substituted aromatic and non-aromatic, single andfused, rings suitably containing up to four hetero-atoms in each ringselected from oxygen, nitrogen and sulphur, which rings may beunsubstituted or C-substituted by, for example, up to three groupsselected from (C₁₋₄)alkylthio; halo; carboxy(C₁₋₄)alkyl;halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl;(C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano, carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; optionally substituted aryl, aryl(C₁₋₄)alkyl oraryl(C₁₋₄)alkoxy and oxo groups.

Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ringatoms. A fused heterocyclic ring system may include carbocyclic ringsand need include only one heterocyclic ring.

Compounds within the invention containing a heterocyclyl group may occurin two or more tautometric forms depending on the nature of theheterocyclyl group; all such tautomeric forms are included within thescope of the invention.

Where an amino group forms part of a single or fused non-aromaticheterocyclic ring as defined above suitable optional substituents insuch substituted amino groups include H; trifluoromethyl; (C₁₋₄)alkyloptionally substituted by hydroxy, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, haloor trifluoromethyl; (C₂₋₄)alkenyl; aryl; aryl (C₁₋₄)alkyl;(C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; formyl; (C₁₋₆)alkylsulphonyl;or aminocarbonyl wherein the amino group is optionally substituted by(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or (C₂₋₄)alkenyl and optionallyfurther substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl.

When used herein the term “aryl”, includes optionally substituted phenyland naphthyl.

Aryl groups may be optionally substituted with up to five, preferably upto three, groups selected from (C₁₋₄)alkylthio; halo;carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl; (C₁₋₄)alkyl;(C₂₋₄)alkenyl; (C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; phenyl, phenyl(C₁₋₄)alkyl or phenyl(C₁₋₄)alkoxy

The term “acyl” includes formyl and (C₁₋₆)alkylcarbonyl group.

Some of the compounds of this invention may be crystallised orrecrystallised from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of the formula(I) or pharmaceutically acceptable derivative thereof.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable derivatives.

Pharmaceutically acceptable derivatives of the above-mentioned compoundsof formula (I) include the free base form or their acid addition orquaternary ammonium salts, for example their salts with mineral acidse.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, ororganic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic,p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid ortartaric acids. Compounds of formula (I) may also be prepared as theN-oxide. Compounds of formula (I) having a free carboxy group may alsobe prepared as an in vivo hydrolysable ester. The invention extends toall such derivatives.

Examples of suitable pharmaceutically acceptable in vivo hydrolysableester-forming groups include those forming esters which break downreadily in the human body to leave the parent acid or its salt. Suitablegroups of this type include those of part formulae (i), (ii), (iii),(iv) and (v):

wherein R^(a) is hydrogen, (C₁₋₆) alkyl, (C₃₋₇) cycloalkyl, methyl, orphenyl, R^(b) is (C₁₋₆) alkyl, (C₁₋₆) alkoxy, phenyl, benzyl, (C₃₋₇)cycloalkyl, (C₃₋₇) cycloalkyloxy, (C₁₋₆) alkyl (C₃₋₇) cycloalkyl,1-amino (C₁₋₆) alkyl, or 1-(C₁₋₆ alkyl)amino (C₁₋₆) alkyl; or R^(a) andR^(b) together form a 1,2-phenylene group optionally substituted by oneor two methoxy groups; R^(c) represents (C₁₋₆) alkylene optionallysubstituted with a methyl or ethyl group and R^(d) and R^(e)independently represent (C₁₋₆) alkyl; R^(f) represents (C₁₋₆) alkyl;R^(g) represents hydrogen or phenyl optionally substituted by up tothree groups selected from halogen, (C₁₋₆) alkyl, or (C₁₋₆) alkoxy; Q isoxygen or NH; R^(h) is hydrogen or (C₁₋₆) alkyl; R^(i) is hydrogen,(C₁₋₆) alkyl optionally substituted by halogen, (C₂₋₆) alkenyl, (C₁₋₆)alkoxycarbonyl, aryl or heteroaryl; or R^(h) and R^(i) together form(C₁₋₆) alkylene; R^(j) represents hydrogen, (C₁₋₆) alkyl or (C₁₋₆)alkoxycarbonyl; and R^(k) represents (C₁₋₈) alkyl, (C₁₋₈) alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkoxy or aryl.

Examples of suitable in vivo hydrolysable ester groups include, forexample, acyloxy(C₁₋₆)alkyl groups such as acetoxymethyl,pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl,1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl;(C₁₋₆)alkoxycarbonyloxy(C₁₋₆)alkyl groups, such asethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl andpropoxycarbonyloxyethyl; di(C₁₋₆)alkylamino(C₁₋₆)alkyl especiallydi(C₁₋₄)alkylamino(C₁₋₄)alkyl groups such as dimethylaminomethyl,dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;2-((C₁₋₆)alkoxycarbonyl)-2-(C₂₋₆)alkenyl groups such as2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl;lactone groups such as phthalidyl and dimethoxyphthalidyl.

A further suitable pharmaceutically acceptable in vivo hydrolysableester-forming group is that of the formula:

wherein R^(k) is hydrogen, C₁₋₆ alkyl or phenyl.

R is preferably hydrogen.

Compounds of formula (I) may also be prepared as the correspondingN-oxides.

Certain of the compounds of formula (I) may exist in the form of opticalisomers, e.g. diastereoisomers and mixtures of isomers in all ratios,e.g. racemic mixtures. The invention includes all such forms, inparticular the pure isomeric forms. For example the invention includescompound in which an A-B group CH(OH)—CH₂ is in either isomericconfiguration, the R-isomer is preferred. The different isomeric formsmay be separated or resolved one from the other by conventional methods,or any given isomer may be obtained by conventional synthetic methods orby stereospecific or asymmetric syntheses.

In a further aspect of the invention there is provided a process forpreparing compounds of formula (I), and pharmaceutically acceptablederivatives thereof, which process comprises reacting a compound offormula (IV) with a compound of formula (V):

wherein n is as defined in formula (1); Z^(1′), Z^(2′), Z^(3′), R^(1′),and R^(3′) are Z¹, Z², Z³, R¹, and R³ as defined in formula (1) orgroups convertible thereto; Z⁴ and Z⁵ are as defined in formula (I);

-   Q¹ is NR^(2′)R^(4′) or a group convertible thereto wherein R^(2′)    and R^(4′) are R² and R⁴ as defined in formula (I) or groups    convertible thereto and Q² is H or R^(3′) or Q¹ and Q² together form    an optionally protected oxo group;-   (i) X is A′-COW, Y is H and n is 0;-   (ii) X is CR⁶═CR⁸R⁹, Y is H and n is 0;-   (iii) X is oxirane, Y is H and n is 0;-   (iv) X is N═C═O and Y is H and n is 0;-   (v) one of X and Y is CO₂R^(y) and the other is CH₂CO₂R^(x);-   (vi) X is CHR⁶R⁷ and Y is C(═O)R⁹;-   (vii) X is CR⁷═PR^(z) ₃ and Y is C(═O)R⁹ and n=1;-   (viii) X is C(═O)R⁷ and Y is CR⁹═PR^(z) ₃ and n=1;-   (ix) Y is COW and X is NHR^(11′), NCO or NR^(11′) COW and n=0 or 1    or when n=1 X is COW and Y is NHR^(11′), NCO or NR^(11′)COW;-   (x) X is NHR^(11′) and Y is C(═O)R⁸ and n=1;-   (xi) X is NHR^(11′) and Y is CR⁸R⁹W and n=1;-   (xii) X is NR^(11′)COCH₂W or NR^(11′)SO₂CH₂W and Y is H and n=0;-   (xiii) X is CR⁶R⁷SO₂W and Y is H and n=0;-   (xiv) X is W or OH and Y is CH₂OH and n is 1;-   (xv) X is NHR^(11′) and Y is SO₂W or X is NR^(11′)SO₂W and Y is H,    and n is 0;-   (xvi) X is W and Y is CONHR^(11′);-   (xvii) X is —CH═CH₂ and Y is H and n=0;-   (xviii) X is CH₃ and Y is H and n=0 together with formaldehyde in    which W is a leaving group, e.g. halo, methanesulphonyloxy,    trifluoromethanesulphonyloxy or imidazolyl; R^(x) and R^(y) are    (C₁₋₆)alkyl; R^(z) is aryl or (C₁₋₆)alkyl; A′ and NR^(11′) are A and    NR¹¹ as defined in formula (I), or groups convertible thereto; and    oxirane is:    wherein R⁶, R⁸ and R⁹ are as defined in formula (I);    and thereafter optionally or as necessary converting Q¹ and Q² to    NR^(2′)R^(4′); converting A′, Z^(1′), Z^(2′), Z^(3′), R^(1′),    R^(2′), R^(3′), R^(4′) and NR^(11′); to A, Z¹, Z², Z³, R¹, R², R³,    R⁴ and NR¹¹; converting A-B to other A-B, interconverting R¹, R², R³    and/or R⁴, and/or forming a pharmaceutically acceptable derivative    thereof.

Process variant (i) initially produces compounds of formula (I) whereinA-B is A′-CO.

Process variant (ii) initially produces compounds of formula (I) whereinA-B is CHR⁶—CR⁸R⁹.

Process variant (iii) initially produces compounds of formula (I)wherein A-B is CR⁶(OH)—CR⁸R⁹.

Process variant (iv) initially produces compounds of formula (I) whereA-B is NH—CO.

Process variant (v) initially produces compounds of formula (I) whereinA-B is CO—CH₂ or CH₂—CO.

Process variant (vi) initially produces compounds of formula (I) whereinA-B is CR⁶R⁷—CR⁹OH.

Process variant (vii) and (viii) initially produce compounds of formula(I) wherein A-B is CR⁷═CR⁹.

Process variant (ix) initially produces compounds of formula (I) whereA-B is CO—NR¹¹ or NR¹¹—CO.

Process variant (x) initially produces compounds of formula (I) whereinA-B is NR¹¹—CHR⁸.

Process variant (xi) initially produces compounds of formula (I) whereinA-B is NR¹¹—CR⁸R⁹.

Process variant (xii) initially produces compounds of formula (I) whereA-B is NR^(11′)—CO or NR^(11′)—SO₂ and n=1.

Process variant (xiii) initially produces compounds of formula (I) whereA-B is CR⁶R⁷—SO₂.

Process variant (xiv) initially produces compounds of formula (I)wherein A-B is O—CH₂.

Process variant (xv) initially produces compounds where AB is NR¹¹SO₂.

Process variant (xvi) initially produces compounds of formula (I) whereA-B is NR^(11′)—CO.

Process variants (xvii) and (xviii) initially produce compounds offormula (I) where A-B is —CH₂—CH₂—.

In process variants (i) and (ix) the reaction is a standard amide orurea formation reaction involving e.g.:

-   1. Activation of a carboxylic acid (e.g. to an acid chloride, mixed    anhydride, active ester, O-acyl-isourea or other species), and    treatment with an amine (Ogliaruso, M. A.; Wolfe, J. F. in The    Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The    Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp    442-8; Beckwith, A. L. J. in The Chemistry of Functional Groups (Ed.    Patai, S.) Suppl. B: The Chemistry of Amides (Ed. Zabricky, J.)    (John Wiley and Sons, 1970), p 73 ff. The acid and amine are    preferably reacted in the presence of an activating agent such as    1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or    1-hydroxybenzotriazole (HOBT) or    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate (HATU); or-   2. The specific methods of:-   a. in situ conversion of an acid into the amine component by a    modified Curtius reaction procedure (Shioiri, T., Murata, M.,    Harnada, Y., Chem. Pharm. Bull. 1987, 35, 2698)-   b. in situ conversion of the acid component into the acid chloride    under neutral conditions (Villeneuve, G. B.; Chan, T. H.,    Tetrahedron. Lett. 1997, 38, 6489).

A′ may be, for example, protected hydroxymethylene.

The process variant (ii) is a standard addition reaction using methodswell known to those skilled in the art. The process is preferablycarried out in a polar organic solvent e.g. acetonitrile in the presenceof an organic base e.g. triethylamine.

In process variant (iii) the coupling may be effected in a suitablesolvent such as acetonitrile or dimethylformamide at room temperature inthe presence of one equivalent of lithium perchlorate as catalyst(general method of J. E. Chateauneuf et al, J. Org. Chem., 56,5939-5942, 1991) or more preferably with ytterbium triflate indichloromethane. In some cases an elevated temperature such as 40-70° C.may be beneficial. Alternatively, the piperidine may be treated with abase, such as one equivalent of butyl lithium, and the resulting saltreacted with the oxirane in an inert solvent such as tetrahydrofuran,preferably at an elevated temperature such as 80° C. Use of a chiralepoxide will afford single diastereomers. Alternatively, mixtures ofdiastereomers may be separated by preparative HPLC or by conventionalresolution through crystallisation of salts formed from chiral acids.

The process variant (iv) is a standard urea formation reaction from thereaction of an isocyanate with an amine and is conducted by methods wellknown to those skilled in the art (for example see March, J; AdvancedOrganic Chemistry, Edition 3 (John Wiley and Sons, 1985), p 802-3). Theprocess is preferably carried out in a polar solvent such asN,N-dimethylformamide.

In process variant (v) the process is two step: firstly a condensationusing a base, preferably sodium hydride or alkoxide, sodamide, alkyllithium or lithium dialkylamide, preferably in an aprotic solvent e.g.ether, THF or benzene; secondly, hydrolysis using an inorganic acid,preferably HCl in aqueous organic solvent at 0-100° C. Analogous routesare described in DE330945, EP31753, EP53964 and H. Sargent, J. Am. Chem.Soc. 68, 2688-2692 (1946). Similar Claisen methodology is described inSoszko et. al., Pr. Kom. Mat. Przyr. Poznan. Tow. Przyj. Nauk., (1962),10, 15.

In process variant (vi) the reaction is carried out in the presence of abase, preferably organometallic or metal hydride e.g. NaH, lithiumdiisopropylamide or NaOEt, preferably in an aprotic solvent, preferablyTHF, ether or benzene at −78 to 25° C. (analogous process in Gutswilleret al. (1978) J. Am. Chem. Soc. 100, 576).

In process variants (vii) and (viii) if a base is used it is preferablyNaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt,sodamide or lithium dialkylamide e.g. di-isopropylamide. An analogousmethod is described in U.S. Pat. No. 3,989,691 and M. Gates et. al.(1970) J. Amer. Chem. Soc., 92, 205, as well as Taylor et al. (1972)JACS 94, 6218.

In process variant (x) where Y is CHO the reaction is a standardreductive alkylation using, e.g., sodium borohydride or sodiumtriacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents forOrganic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p4649).

The process variant (xi) is a standard alkylation reaction well known tothose skilled in the art, for example where an alcohol or amine istreated with an alkyl halide in the presence of a base (for example seeMarch, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons,1985), p 364-366 and p 342-343). The process is preferably carried outin a polar solvent such as N,N-dimethylformamide

In process variant (xii) the reaction is an alkylation, examples ofwhich are described in J. Med. chem. (1979) 22(10) 1171-6. The compoundof formula (IV) may be prepared from the corresponding compound where Xis NHR^(11′) by acylation with an appropriate derivative of the acidWCH₂COOH such as the acid chloride or sulphonation with an appropriatederivative of the sulphonic acid WCH₂SO₃H such as the sulphonylchloride.

In process variant (xiii) the reaction is a standard sulphonamideformation reaction well known to those skilled in the art. This may bee.g. the reaction of a sulphonyl halide with an amine.

In process variant (xiv) where X is W such as halogen,methanesulphonyloxy or trifluoromethanesulphonyloxy, the hydroxy groupin Y is preferably converted to an OM group where M is an alkali metalby treatment of an alcohol with a base. The base is preferably inorganicsuch as NaH, lithium diisopropylamide or sodium. Where X is OH, thehydroxy group in Y is activated under Mitsunobu conditions (Fletcher etal. J Chem Soc. (1995), 623). Alternatively the X═O and Y═CH₂OH groupscan be reacted directly by activation with 1,3-dicyclohexylcarbodiimide(DCC) (Chem. Berichte 1962, 95, 2997 or Angewante Chemie 1963 75, 377).

In process variant (xv) the reaction is conducted in the presence of anorganic base such as triethylamine or pyridine such as described byFuhrman et.al., J. Amer. Chem. Soc.; 67, 1245, 1945. The X═NR^(11′)SO₂Wor Y═SO₂W intermediates can be formed from the requisite amine e.g. byreaction with SO₂Cl₂ analogously to the procedure described by the sameauthors Fuhrman et.al., J. Amer. Chem. Soc.; 67, 1245, 1945.

In process variant (xvi) the leaving group W is preferably chloro, bromoor iodo or trifluoromethylsulphonyloxy and the reaction is the palladiumcatalysed process known as the “Buchwald” reaction (J. Yin and S. L.Buchwald, Org. Lett., 2000, 2, 1101).

In process variant (xvii) the reaction is the addition of an amine to anolefin which is susceptible to nucleophilic attack.

In process variant (xviii) the reaction is a three componentcondensation reaction carried out under mildly acidic conditions.

Reduction of a carbonyl group A or B to CHOH can be readily accomplishedusing reducing agents well known to those skilled in the art, e.g.sodium borohydride in aqueous ethanol or lithium aluminium hydride inethereal solution. This is analogous to methods described in EP53964,U.S. Pat. No. 384,556 and J. Gutzwiller et al, J. Amer. Chem. Soc.,1978, 100, 576.

The carbonyl group A or B may be reduced to CH₂ by treatment with areducing agent such as hydrazine in ethylene glycol, at e.g. 130-160°C., in the presence of potassium hydroxide.

Reaction of a carbonyl group A or B with an organometallic reagentyields a group where R⁶ or R⁸ is OH and R⁷ or R⁹ is alkyl.

A hydroxy group on A or B may be oxidised to a carbonyl group byoxidants well known to those skilled in the art, for example, manganesedioxide, pyridinium chlorochromate or pyridinium dichromate.

A hydroxyalkyl A-B group CHR⁷CR⁹OH or CR⁷(OH)CHR⁹ may be dehydrated togive the group CR⁷═CR⁹ by treatment with an acid anhydride such asacetic anhydride.

Methods for conversion of CR⁷═CR⁹ by reduction to CHR⁷CHR⁹ are wellknown to those skilled in the art, for example using hydrogenation overpalladium on carbon as catalyst. Methods for conversion of CR⁷═CR⁹ togive the A-B group CR⁷(OH)CHR⁹ or CHR⁷CR⁹OH are well known to thoseskilled in the art for example by epoxidation and subsequent reductionby metal hydrides, hydration, hydroboration or oxymercuration.

An amide carbonyl group may be reduced to the corresponding amine usinga reducing agent such as lithium aluminium hydride.

A hydroxy group in A or B may be converted to azido by activation anddisplacement e.g. under Mitsunobu conditions using hydrazoic acid or bytreatment with diphenylphosphorylazide and base, and the azido group inturn may be reduced to amino by hydrogenation.

An example of a group Q¹ convertible to NR² R⁴ is NR^(2′)R^(4′) orhalogen. Halogen may be displaced by an amine HNR^(2′)R^(4′) by aconventional alkylation.

When Q¹Q² together form a protected oxo group this may be an acetal suchas ethylenedioxy which can subsequently be removed by acid treatment togive a compound of formula (VI):

wherein the variables are as described for formula (I)

The ketone of formula (VI) is reacted with an amine HNR^(2′)R^(4′) byconventional reductive alkylation as described above for process variant(x).

Examples of groups Z^(1′), Z^(2′) and Z^(3′) convertible to Z¹, Z² andZ³ include CR¹ or CR^(1′)CR^(1a′) where R^(1′) and R^(1a′) are groupsconvertible to R¹ and R^(1a). Z^(1′), Z^(2′) and Z^(3′) are preferablyZ¹, Z² and Z³.

R^(1a′), R^(1′) and R^(2′) are preferably R^(1a), R¹ and R². R^(2′) ispreferably hydrogen. R^(3′) is R³ or more preferably hydrogen, vinyl,alkoxycarbonyl or carboxy. R⁴ is R⁴ or more preferably H or anN-protecting group such as t-butoxycarbonyl, benzyloxycarbonyl or9-fluorenylmethyloxycarbonyl.

Conversions of R^(1′), R^(1a′), R^(2′), R³ and R⁴ and interconversionsof R¹, R^(1a), R², R³ and R⁴ are conventional. In compounds whichcontain an optionally protected hydroxy group, suitable conventionalhydroxy protecting groups which may be removed without disrupting theremainder of the molecule include acyl and alkylsilyl groups.N-protecting groups are removed by conventional methods.

For example R^(1′) methoxy is convertible to R^(1′) hydroxy by treatmentwith lithium and diphenylphosphine (general method described in Irelandet al, J. Amer. Chem. Soc., 1973, 7829) or HBr. Alkylation of thehydroxy group with a suitable alkyl derivative bearing a leaving groupsuch as halide and a protected amino, piperidyl, amidino or guanidinogroup or group convertible thereto, yields, afterconversion/deprotection, R¹ alkoxy substituted by optionallyN-substituted amino, piperidyl, guanidino or amidino.

R³ alkenyl is convertible to hydroxyalkyl by hydroboration using asuitable reagent such as 9-borabicyclo[3.3.1]nonane, epoxidation andreduction or oxymercuration.

R³ 1,2-dihydroxyalkyl can be prepared from R^(3′) alkenyl using osmiumtetroxide or other reagents well known to those skilled in the art (seeAdvanced Organic Chemistry, Ed. March, J., John Wiley and Sons, 1985, p732-737 and refs. cited therein) or epoxidation followed by hydrolysis(see Advanced Organic Chemistry, Ed. March, J. John Wiley and Sons,1985, p 332, 333 and refs. cited therein).

R³ vinyl can be chain extended by standard homologation, e.g. byconversion to hydroxyethyl followed by oxidation to the aldehyde, whichis then subjected to a Wittig reaction.

Opening an epoxide-containing R^(3′) group with cyanide anion yields aCH(OH)—CH₂CN group.

Opening an epoxide-containing R^(3′) group with azide anion yields anazide derivative which can be reduced to the amine. Conversion of theamine to a carbamate is followed by ring closure with base to give the2-oxo-oxazolidinyl containing R³ group.

Substituted 2-oxo-oxazolidinyl containing R³ groups may be prepared fromthe corresponding aldehyde by conventional reaction with a glycine anionequivalent, followed by cyclisation of the resulting amino alcohol (M.Grauert et al, Ann. Chem., 1985, 1817; Rozenberg et al, Angew. Chem.Int. Ed. Engl., 1994, 33(1), 91). The resulting 2-oxo-oxazolidinyl groupcontains a carboxy group which can be converted to other R¹⁰ groups bystandard procedures.

Carboxy groups within R³ may be prepared by Jones' oxidation of thecorresponding alcohols CH₂OH using chromic acid and sulphuric acid inwater/methanol (E. R. H. Jones et al, J. Chem. Soc., 1946, 39). Otheroxidising agents may be used for this transformation such as sodiumperiodate catalysed by ruthenium trichloride (G. F. Tutwiler et al, J.Med. Chem., 1987, 30(6), 1094), chromium trioxide-pyridine (G. Just etal, Synth. Commun., 1979, 9(7), 613), potassium permanganate (D. E.Reedich et al, J. Org. Chem., 1985, 50(19), 3535), and pyridiniumchlorochromate (D. Askin et al, Tetrahedron Lett., 1988, 29(3), 277).

The carboxy group may alternatively be formed in a two stage process,with an initial oxidation of the alcohol to the corresponding aldehydeusing for instance dimethyl sulphoxide activated with oxalyl chloride(N. Cohen et al, J. Am. Chem. Soc., 1983, 105, 3661) ordicyclohexylcarbodiimide (R. M. Wengler, Angew. Chim. Int. Ed. Eng.,1985, 24(2), 77), or oxidation with tetrapropylammonium perruthenate(Ley et al, J. Chem. Soc. Chem Commun., 1987, 1625). The aldehyde maythen be separately oxidised to the corresponding acid using oxidisingagents such as silver (II) oxide (R. Grigg et al, J. Chem. Soc. Perkin1, 1983, 1929), potassium permanganate (A. Zurcher, Helv. Chim. Acta.,1987, 70 (7), 1937), sodium periodate catalysed by ruthenium trichloride(T. Sakata et al, Bull. Chem. Soc. Jpn., 1988, 61(6), 2025), pyridiniumchlorochromate (R. S. Reddy et al, Synth. Commun., 1988, 18(51), 545) orchromium trioxide (R. M. Coates et al, J. Am. Chem. Soc., 1982, 104,2198).

An R³ CO₂H group may also be prepared from oxidative cleavage of thecorresponding diol, CH(OH)CH₂OH, using sodium periodate catalysed byruthenium trichloride with an acetonitrile-carbontetrachloride-watersolvent system (V. S. Martin et al, Tetrahedron Letters, 1988, 29(22),2701).

Other routes to the synthesis of carboxy groups within R³ are well knownto those skilled in the art.

R³ groups containing a cyano or carboxy group may also be prepared byconversion of an alcohol to a suitable leaving group such as thecorresponding tosylate by reaction with para-toluenesulphonyl chloride(M. R. Bell, J. Med. Chem., 1970, 13, 389), or the iodide usingtriphenylphosphine, iodine, and imidazole (G. Lange, Synth. Commun.,1990, 20, 1473). The second stage is the displacement of the leavinggroup with cyanide anion (L. A. Paquette et al, J. Org. Chem., 1979,44(25). 4603; P. A. Grieco et al, J. Org. Chem., 1988, 53(16), 3658.Finally acidic hydrolysis of the nitrile group gives the desired acids(H. Rosemeyer et al, Heterocycles, 1985, 23 (10), 2669). The hydrolysismay also be carried out with base e.g. potassium hydroxide (H. Rapoport,J. Org. Chem., 1958, 23, 248) or enzymatically (T. Beard et al,Tetrahedron Asymmetry, 1993, 4 (6), 1085).

R³ cis or trans hydroxy may be introduced by the methods of van Deale etal., Drug Development Research 8:225-232 (1986) or Heterocycles 39(1),163-170 (1994). For trans hydroxy, a suitable method convertsN-protected tetrahydropyridine to the epoxide by treatment withmetachloroperbenzoic acid, followed by opening of the epoxide with asuitable amine NR^(2′)R^(4′). R^(3′) hydroxy may then be converted tooptionally substituted amino via preparation of the R^(3′) aminoderivative by standard transformations such as a Mitsunobu reaction (forexample as reviewed in Misunobu, Synthesisi, (1981), 1), for examplewith succinimide in the presence of diethylazodicarboxylate andtriphenylphosphine to give the phthalimidoethylpiperidine. Removal ofthe phthaloyl group, for example by treatment with methylhydrazine,affords the R^(3′) amine. Optional substitution may then be introducedby standard methods for amine substitution well known to those skilledin the art.

R³ 4-CF₃ may be introduced by the following scheme I:

Commercially-available ethyl isonipecotate (I-1) reacts with anappropriate acylating agent, preferably di-tert-butyl dicarbonate, toafford the protected derivative I-2. Typical solvents for this reactioninclude CH₂Cl₂, THF, or DMF. The protecting group for the amine must becompatible with subsequent chemistry, and must be readily removable whendesired. Methods for the protection of amines are well-known to those ofskill in the art, and are described in standard reference volumes, suchas Greene “Protective Groups in Organic Synthesis” (published byWiley-Interscience). Alkylation of I-2 can be accomplished by reactionwith an appropriate base, typically LDA or LiN(TMS)₂, in an aproticsolvent, usually THF or DME, followed by trapping of the enolate with anappropriate electrophile, to afford I-3. Trifluoromethyl iodide (CF₃I)or S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate aretypically preferred as electrophilic trifluoromethylating reagents. Theethyl ester of I-3 is hydrolyzed using aqueous base, for example, LiOHin aqueous THF or NaOH in aqueous methanol or ethanol, and theintermediate carboxylate salt is acidified with a suitable acid, forinstance TFA or HCl, to afford the carboxylic acid I-4. Curtius-typerearrangement of I-4 gives an intermediate isocyanate, which typicallyis not isolated, but rather is reacted in situ with an appropriatealcohol, such as benzyl alcohol, to give I-5. Diphenylphosphoryl azidein the presence of an amine base, generally triethylamine ordiisopropylethylamine (Hunig's base), is the preferred reagentcombination for effecting the Curtius-type rearrangement of I-4, butmore classical conditions, such as formation of the acid chloride,reaction with azide anion, and warming of the acyl azide, can also beused. The benzyloxycarbonyl group in I-5 is removed by hydrogenolysis inthe presence of a palladium catalyst, typically palladium on activatedcharcoal, in a suitable solvent, usually EtOH, MeOH, EtOAc, or mixturesthereof, to give amine I-6.

R³ 2-CF₃ may be introduced by the following scheme II:

Imine II-1, prepared in standard fashion by acid-catalyzed reaction oftrifluoroacetaldehyde ethyl hemiacetal and (R)-(+)-α-methylbenzylamine,reacts with a silyloxydiene, for example1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene, in a Diels-Alder reactionto afford piperidone II-2. The reaction is conducted in a neutralsolvent such as CH₃CN, THF, or CH₂Cl₂, and oftentimes is mediated by aLewis acid such as ZnCl₂. Diastereomers are best separated at thispoint. The enone II-2 is reduced to the corresponding ketone II-3 byreaction with L-Selectride® in a suitable solvent, generally THF or DME,and the ketone is converted to an oxime derivative under standardconditions well-known to those of skill in the art. Reduction of theoxime derivative under standard conditions (LiAlH₄) gives a mixture ofdiastereomeric amines from which the amine II-5 can be isolated. Theamine is protected with an appropriate protecting group, preferably atert-butyl carbamate (see Scheme I), to afford II-6. The α-methylbenzylgroup of II-6 is removed by hydrogenolysis in the presence of apalladium catalyst, typically palladium on activated charcoal, in asuitable solvent, usually EtOH, MeOH, EtOAc, or mixtures thereof, togive amine II-7.

R³ 3-CF₃ may be introduced by the following scheme III:

The commercially-available ketone III-1 is converted to thecorresponding silly enroll ether III-2 by reaction with a silylatingreagent, such a trimethylsilyl chloride or trimethylsilyl triflate, inthe presence of an amine base, typically triethylamine, in a suitablesolvent, such as diethyl ether, THF, DMF, or mixtures thereof. The sillyenroll ether III-2 reacts with an electrophilic trifluoromethylatingreagent, such as trifluoromethyl iodide (CF₃I) or more preferablyS-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (seeTet. Lett. 1990, 31, 3579-3582)), in an appropriate solvent, such asTHF, DMF, or mixtures thereof, to afford the α-trifluoromethyl ketoneIII-3. Ketone III-3 reacts with a chiral amine, for instance(R)-(+)-α-methylbenzylamine, under standard acidic catalysis, to affordthe imine derivative III-4, which can be reduced to afford amine III-5.This type of reduction is typically conducted using sodium borohydride,sodium cyanoborohydride or sodium (triacetoxy)borohydride, in anappropriate solvent, such as EtOH, MeOH, THF, CH₂Cl₂, ClCH₂CH₂Cl, ormixtures thereof. Diastereomers are best separated at this point. Theα-methylbenzyl group of III-5 is removed by hydrogenolysis in thepresence of a palladium catalyst, typically palladium on activatedcharcoal, in a suitable solvent, usually EtOH, MeOH, EtOAc, or mixturesthereof, to give amine III-6.

R³ 2-oxo may be introduced by the following scheme IV:

(R,S)-4-(Dibenzylamino)piperidin-2-one (IV-2, Homo-Freidinger Lactam,prepared from (R,S)-aspartic acid according to the procedure of Weberand Gmeiner, Synlett, 1998, 885-887) reacts with an appropriate epoxide,for instance 6-methoxy-4-(R)-oxiranylquinoline (VI-1) or6-methoxy-4-(R)-oxiranyl-[1,5]naphthyridine, to afford the adduct IV-3.The reaction is mediated by a strong base, preferably sodium hydride,which is used to deprotonate IV-2, and is typically conducted in apolar, aprotic solvent, such as THF, DMF, or mixtures thereof. Thebenzyl groups in IV-3 are removed by hydrogenolysis in the presence of apalladium catalyst, typically palladium on activated charcoal, in asuitable solvent, usually EtOH, MeOH, EtOAc, or mixtures thereof, togive amine IV-4.

R³ 3-F may be introduced by the following scheme V:

The enol ether (V-2), prepared from commercially-availableN-(tert-butoxycarbonyl)piperidone (V-1) as described in Scheme III,reacts with an electrophilic fluorinating reagent, preferablySelectfluorin™ (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate), in a neutral solvent such as CH₃CN, to affordthe α-fluoro ketone V-3. Reductive amination of V-3 with benzylamineaccording to the procedures described in Schemes I and III gives theexpected 4-aminobenzyl-3-fluoro-N-(tert-butoxycarbonyl)piperidinederivatives V-4 and V-5 as a mixture of cis- and trans-isomers in an 8:1ratio. These diastereomers are separable by chromatography on silicagel. The predominate cis-mixture of enantiomers is debenzylated bycatalytic hydrogenation as described in Scheme II, to give the aminoderivative V-6.

Other functional groups in R³ may be obtained by conventionalconversions of hydroxy, carboxy or cyano groups.

Tetrazoles are conveniently prepared by reaction of sodium azide withthe cyano group (e.g. F. Thomas et al, Bioorg. Med. Chem. Lett., 1996,6(6), 631; K. Kubo et al, J. Med. Chem., 1993, 36, 2182) or by reactionof azidotri-n-butyl stannane with the cyano group followed by acidichydrolysis (P. L. Ornstein, J. Org. Chem., 1994, 59, 7682 and J. Med.Chem., 1996, 39 (11), 2219).

The 3-hydroxy-3-cyclobutene-1,2-dion-4-yl group (e.g. R. M. Soll,Bioorg. Med. Chem. Lett., 1993, 3(4), 757 and W. A. Kinney, J. Med.Chem., 1992, 35(25), 4720) can be prepared by the followingsequence:—(1) a compound where R³ is (CH₂)_(n)CHO (n=0, 1, 2) is treatedwith triethylamine, carbon tetrabromide/triphenylphosphine to giveinitially (CH₂)_(n)CH═CHBr; (2) dehydrobromination of this intermediateto give the corresponding bromoethyne derivative (CH₂)_(n)C≡CBr (forthis 2 stage sequence see D. Grandjean et al, Tetrahedron Lett., 1994,35(21), 3529); (3) palladium-catalysed coupling of the bromoethyne with4-(1-methylethoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-1,2-dione(Liebeskind et al, J. Org. Chem., 1990, 55, 5359); (4) reduction of theethyne moiety to —CH₂CH₂— under standard conditions of hydrogen andpalladium on charcoal catalysis(see Howard et al, Tetrahedron, 1980, 36,171); and finally (4) acidic hydrolysis of the methyl ethoxyester togenerate the corresponding 3-hydroxy-3-cyclobutene-1,2-dione group (R.M. Soll, Bioorg. Med. Chem. Lett., 1993, 3(4, 757).

The tetrazol-5-ylaminocarbonyl group may be prepared from thecorresponding carboxylic acid and 2-aminotetrazole by dehydration withstandard peptide coupling agents such as 1,1′-carbonyldiimidazole (P. L.Ornstein et al, J. Med Chem, 1996, 39(11), 2232).

The alkyl- and alkenyl-sulphonylcarboxamides are similarly prepared fromthe corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamideby dehydration with standard peptide coupling agents such as1,1′-carbonyldiimidazole (P. L. Ornstein et al, J. Med. Chem., 1996,39(11), 2232).

The hydroxamic acid groups are prepared from the corresponding acids bystandard amide coupling reactions e.g. N. R. Patel et al, Tetrahedron,1987, 43(22), 5375.

2,4-Thiazolidinedione groups may prepared from the aldehydes bycondensation with 2,4-thiazolidinedione and subsequent removal of theolefinic double bond by hydrogenation.

The preparation of 5-oxo-1,2,4-oxadiazoles from nitrites is described byY. Kohara et al, Bioorg. Med. Chem. Lett., 1995, 5(17). 1903.

1,2,4-Triazol-5-yl groups may be prepared from the corresponding nitrileby reaction with an alcohol under acid conditions followed by reactionwith hydrazine and then an R¹⁰-substituted activated carboxylic acid(see J. B. Polya in “Comprehensive Heterocyclic Chemistry” Edition 1, p762, Ed A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984 andJ. J. Ares et al, J. Heterocyclic Chem., 1991, 28(5), 1197).

Other substituents on R³ alkyl or alkenyl may be interconverted byconventional methods, for example hydroxy may be derivatised byesterification, acylation or etherification. Hydroxy groups may beconverted to halogen, thiol, alkylthio, azido, alkylcarbonyl, amino,aminocarbonyl, oxo, alkylsulphonyl, alkenylsulphonyl or aminosulphonylby conversion to a leaving group and substitution by the required groupor oxidation as appropriate or reaction with an activated acid,isocyanate or alkoxyisocyanate. Primary and secondary hydroxy groups canbe oxidised to an aldehyde or ketone respectively and alkylated with asuitable agent such as an organometallic reagent to give a secondary ortertiary alcohol as appropriate. A carboxylate group may be converted toan hydroxymethyl group by reduction of an ester of this acid with asuitable reducing agent such as lithium aluminium hydride.

An NH₂ substituent on piperidine is converted to NR²R⁴ by conventionalmeans such as amide or sulphonamide formation with an acyl derivativeR⁵COW or R⁵SO₂W, for compounds where U is CO or SO₂ or, where U is CH₂,by alkylation with an alkyl halide R⁵CH₂-halide in the presence of base,acylation/reduction with an acyl derivative R⁵COW or reductivealkylation with an aldehyde R⁵CHO.

Where one of R³ and R⁶, R⁷, R⁸ or R⁹ contains a carboxy group and theother contains a hydroxy or amino group they may together form a cyclicester or amide linkage. This linkage may form spontaneously duringcoupling of the compound of formula (IV) and the piperidine moiety or inthe presence of standard peptide coupling agents.

It will be appreciated that under certain circumstances interconvertionsmay interfere, for example, A or B hydroxy groups in A or B and thepiperidine substituent NH₂ will require protection e.g. as a carboxy- orsilyl-ester group for hydroxy and as an acyl derivative for piperidineNH₂, during conversion of R^(1′), R^(2′), R^(3′) or R^(4′), or duringthe coupling of the compounds of formulae (IV) and (V).

Compounds of formulae (IV) and (V) are known compounds, (see for exampleSmith et al, J. Amer. Chem. Soc., 1946, 68, 1301) or preparedanalogously.

Compounds of formula (IV) where X is CR⁶R⁷SO₂W may be prepared by aroute analogous to that of Ahmed El Hadri et al, J. Heterocyclic Chem.,1993, 30(3), 631. Thus compounds of formula (IV) where X is CH₂SO₂OH maybe prepared by reacting the corresponding 4-methyl compound withN-bromosuccinimide, followed by treatment with sodium sulfite. Theleaving group W may be converted to another leaving group W, e.g. ahalogen group, by conventional methods.

The isocyanate of formula (IV) may be prepared conventionally from a4-amino derivative such as 4-amino-quinoline, and phosgene, or phosgeneequivalent (eg triphosgene) or it may be prepared more conveniently froma 4-carboxylic acid by a “one-pot” Curtius Reaction with diphenylphosphoryl azide (DPPA) [see T. Shiori et al. Chem. Pharm. Bull. 35,2698-2704 (1987)].

The 4-amino derivatives are commercially available or may be prepared byconventional procedures from a corresponding 4-chloro or4-trifluoromethanesulphonate derivative by treatment with ammonia (O. G.Backeberg et. al., J. Chem Soc., 381, 1942) or propylamine hydrochloride(R. Radinov et. al., Synthesis, 886, 1986).

4-Alkenyl compounds of formula (IV) may be prepared by conventionalprocedures from a corresponding 4-halogeno-derivative by e.g. a Hecksynthesis as described in e.g. Organic Reactions, 1982, 27, 345.

4-Halogeno derivatives of compounds of formula (IV) are commerciallyavailable, or may be prepared by methods known to those skilled in theart. A 4-chloroquinoline is prepared from the correspondingquinolin-4-one by reaction with phosphorus oxychloride (POCl₃) orphosphorus pentachloride, PCl₅. A 4-chloroquinazoline is prepared fromthe corresponding quinazolin-4-one by reaction with phosphorusoxychloride (POCl₃) or phosphorus pentachloride, PCl₅. A quinazolinoneand quinazolines may be prepared by standard routes as described by T.A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R. C.Elderfield.

4-Carboxy derivatives of compounds of formula (IV) are commerciallyavailable or may be prepared by conventional procedures for preparationof carboxy heteroaromatics well known to those skilled in the art. Forexample, quinazolines may be prepared by standard routes as described byT. A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R. C.Elderfield. These 4-carboxy derivatives maybe activated by conventionalmeans, e.g. by conversion to an acyl halide or anhydride.

Pyridazines may be prepared by routes analogous to those described inComprehensive Heterocyclic Chemistry, Volume 3, Ed A. J. Boulton and A.McKillop and napthyridines may be prepared by routes analogous to thosedescribed in Comprehensive Heterocyclic Chemistry, Volume 2, Ed A. J.Boulton and A. McKillop.

A 4-oxirane derivative of compounds of formula (IV) is convenientlyprepared from the 4-carboxylic acid by first conversion to the acidchloride with oxalyl chloride and then reaction withtrimethylsilyldiazomethane to give the diazoketone derivative.Subsequent reaction with 5M hydrochloric acid gives thechloromethylketone. Reduction with sodium borohydride in aqueousmethanol gives the chlorohydrin which undergoes ring closure to affordthe epoxide on treatment with base, e.g. potassium hydroxide inethanol-tetrahydrofuran.

Alternatively and preferably, 4-oxirane derivatives can be prepared frombromomethyl ketones which can be obtained from 4-hydroxy compounds byother routes well known to those skilled in he art. For example, hydroxycompounds can be converted to the corresponding4-trifluoromethanesulphonates by reaction with trifluoromethanesulphonicanhydride under standard conditions (see K. Ritter, Synthesis, 1993,735). Conversion into the corresponding butyloxyvinyl ethers can beachieved by a Heck reaction with butyl vinyl ether under palladiumcatalysis according to the procedure of W. Cabri et al, J. Org. Chem,1992, 57 (5), 1481. (Alternatively, the equivalent intermediates can beattained by Stille coupling of the trifluoromethanesulphonates or theanalogous chloro derivatives with (1-ethoxyvinyl)tributyl tin, (T. R.Kelly, J. Org. Chem., 1996, 61, 4623).) The alkyloxyvinyl ethers arethen converted into the corresponding bromomethylketones by treatmentwith N-bromosuccinimide in aqueous tetrahydrofuran in a similar mannerto the procedures of J. F. W. Keana, J. Org. Chem., 1983, 48, 3621 andT. R. Kelly, J. Org. Chem., 1996, 61, 4623.

The 4-hydroxyderivatives can be prepared from an aminoaromatic byreaction with methylpropiolate and subsequent cyclisation, analogous tothe method described in N. E. Heindel et al, J. Het. Chem., 1969, 6, 77.For example, 5-amino-2-methoxy pyridine can be converted to4-hydroxy-6-methoxy-[1,5]naphthyridine using this method.

If a chiral reducing agent such as (+) or(−)-B-chlorodiisopinocamphenylborane [‘DIP-chloride’] is substituted forsodium borohydride, the prochiral chloromethylketone is converted intothe chiral chlorohydrin with ee values generally 85-95% [see C. Bohm etal, Chem. Ber. 125, 1169-1190, (1992)]. Recrystallisation of the chiralepoxide gives material in the mother liquor with enhanced optical purity(typically ee 95%).

The (R)-epoxide, when reacted with a piperidine derivative givesethanolamine compounds as single diastereomers with (R)-stereochemistryat the benzylic position.

Alternatively, the epoxide may be prepared from the 4-carboxaldehyde bya Wittig approach using trimethylsulfonium iodide [see G. A. Epling andK-Y Lin, J. Het. Chem., 1987, 24, 853-857], or by epoxidation of a4-vinyl derivative.

4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridinederivatives by reaction with diethyl ethoxymethylene malonate to producethe 4-hydroxy-3-carboxylic acid ester derivative with subsequenthydrolysis to the acid, followed by thermal decarboxylation in quinoline(as for example described for 4-Hydroxy-[1,5]naphthyridine-3-carboxylicacid, J. T. Adams et al., J. Amer. Chem. Soc., 1946, 68, 1317). A4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivativeby heating in phosphorus oxychloride, or to the 4-methanesulphonyloxy or4-trifluoromethanesulphonyloxy derivative by reaction withmethanesulphonyl chloride or trifluoromethanesulphonic anhydride,respectively, in the presence of an organic base. A 4-amino1,5-naphthyridine can be obtained from the 4-chloro derivative byreaction with n-propylamine in pyridine.

Similarly, 6-methoxy-1,5-naphthyridine derivatives can be prepared from3-amino-6-methoxypyridine.

1,5-Naphthyridines may be prepared by other methods well known to thoseskilled in the art (for examples see P. A. Lowe in “ComprehensiveHeterocyclic Chemistry” Volume 2, p 581-627, Ed A. R. Katritzky and C.W. Rees, Pergamon Press, Oxford, 1984).

The 4-hydroxy and 4-amino-cinnolines may be prepared following methodswell known to those skilled in the art [see A. R. Osborn and K.Schofield, J. Chem. Soc. 2100 (1955)]. For example, a2-aminoacetophenone is diazotised with sodium nitrite and acid toproduce the 4-hydroxycinnoline with conversion to chloro and aminoderivatives as described for 1,5-naphthyridines.

R^(A) groups where the ring (y) is 4-pyridyl are available by thesequence described below, starting from an aromatic or heterocyclicamine (1), with at least one free CH position adjacent to the amine.Reaction with Meldrum's acid and trimethyl orthformate in ethanol atreflux affords the corresponding2,2-dimethyl-5-phenylaminomethylene-[1,3]dioxane-4,6-dione derivatives(2). These can be cyclised at elevated temperatures (180-220° C.) ininert solvents such as Dowtherm to give the corresponding1H-quinolin-4-one (3) or heterocyclic analogues eg1H-[1,6]naphthyridin-4-one. These processes are well-established and aredescribed by Walz and Sundberg (J. Org. Chem., 2000, 65 (23), 8001) andby Todter and Lackner (Synthesis, 1997 (5) 576).

Activation of the quinolone species related to (3) into thecorresponding 4-quinolyl bromides (4) can be accomplished withphosphorous oxybromide or more preferably phosphorous tribromide inN,N-dimethylformamide (see M. Schmittel et al, Synlett, 1997, (9), 1096and K. Gould et al, J. Med., Chem., 1988, 31 (7), 1445). Thecorresponding chlorides (5) are available by using phosphoryloxychloride (for instance C. W. Wright et al, J. Med., Chem., 2001, 44(19), 3187).

Alternatively, the quinolone species may be activated to thecorresponding 1,1,1-trifluoro-methanesulfonic acid quinolin-4-yl esters(6) by the action of agents such as triflic anhydride or more preferablyN-trifluoromethanesulphonimide (see for example M. Alvarez et al, Tet2000, 56 (23) 3703; M. Alvarez et al, Eur. J. Org., Chem., 2000, (5),849; J. Joule et al, Tet, 1998, 54 (17), 4405; J. K. Stille et al,J.A.C.S., 1988, 110 (12), 4051).

Activated species such as (4), (5), and (6) can then be subjected to avariety of metal-catalysed coupling reactions, such as amidation withprimary carboxamides to give compounds such as (7) following theprocedures of S. L. Buchwald et al (J.A.C.S., 2001, 123, 4051 and 7727;Org. Lett., 1999, 1, 35) or Sonogashira coupling with acetylenes to givecompounds such as (8) (see A. Droz et al, Helv. Chim. Acta., 2001, 84(8), 2243; M. Belly et al, Synlett, 2001 (2), 222; M. Pirrung et al,J.A.C.S., 2001, 123 (16), 3638).

R^(A) thieno[3,2-b]pyridin-7-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinolin-8-yl andisoquinolin-5-yl derivatives are commercially available or prepared byconventional methods from commercially available or literaturederivatives, for example 4H-thieno[3,2-b]pyridin-4-one,2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (prepared by the method of H.Neunhoffer et al, Chem., Ber., 1990, 123), 2-methoxy-quinolin-8-ylamine(prepared by the method of K. Mislow et al J.A.C.S. 68, 1353 (1946)),2,8-quinolinediol or trifluoromethane sulphonic acid-isoquinolin-5-ylester (prepared as in D. Ortwine et al, J. Med. Chem., 1992, 35 (8),1345).

R^(A) quinoxalin-5-yl derivatives may be obtained from 2- or3-methylquinoxalin-5-ol prepared as described by Y. Abe et al, J. Med.Chem., 1998, 41 (21), 4062 or from suitable substituted derivativesprepared by analogous methods. R^(A) 3-methoxyquinoxaline-5-ylderivatives may be obtained from 3-oxoquinoxalin-5-yl prepared by thegeneral methods of F. J. Wolf et al., J.A.C.S. 1949, 71, 6, using asuitable methylating agent such as trimethylsilyl(diazomethane). Thecorresponding 1,2,3,4-tetrahydro-quinoxalin-5-yl may be prepared byreduction with a suitable reducing agent such as sodium cyanoborohydridein the presence of an acid such as acetic acid.

The isoquinolin-8-yl system can be prepared from the appropriatelysubstituted benzylamine by cyclocondensation with diethoxy-acetaldehyde(see, for example, K. Kido and Y. Watanabe, Chemical & PharmaceuticalBulletin, 35(12), 4964-6; 1987). Alternatively 8-bromo-isoquinoline(prepared by the method of F. T. Tyson, J.A.C.S., 1939, 61, N. Briet etal., Tetrahedron (2002), 58(29), 5761-5766 or W. D. Brown, et al.,Synthesis (2002), (1), 83-86. 183 can be subjected to N-oxidation andrearrangement to give 8-bromo-2H-isoquinolin-1-one. This can beN-methylated to give 8-bromo-2-methyl-2H-isoquinolin-1-one, anappropriate intermediate for the2-methyl-1-oxo-1,2-dihydroisoquinolin-8-yl system.

The 1-methoxy-isoquinolin-8-yl system can also be obtained from the8-bromoisoquinoline-N-oxide above by rearrangement with methylchloroformate to give 8-bromo-1-methoxy-isoquinoline, an appropriateintermediate for the 1-methoxy-isoquinolin-8-yl system.

For compounds of formula (V), suitable amines may be prepared from thecorresponding 4-substituted piperidine acid or alcohol. In a firstinstance, an N-protected piperidine containing an acid bearingsubstituent, can undergo a Curtius rearrangement and the intermediateisocyanate can be converted to a carbamate by reaction with an alcohol.Conversion to the amine may be achieved by standard methods well knownto those skilled in the art used for amine protecting group removal. Forexample, an acid substituted N-protected piperidine can undergo aCurtius rearrangement e.g. on treatment with diphenylphosphoryl azideand heating, and the intermediate isocyanate reacts in the presence of2-trimethylsilylethanol to give the trimethylsilylethylcarbamate (T. L.Capson & C. D. Poulter, Tetrahedron Lett., 1984, 25, 3515). Thisundergoes cleavage on treatment with tetrabutylammonium fluoride to givethe 4-amine substituted N-protected piperidine.

In a second instance, an N-protected piperidine containing an alcoholbearing substituent undergoes a Mitsunobu reaction (for example asreviewed in Mitsunobu, Synthesis, (1981), 1), for example withsuccinimide in the presence of diethyl azodicarboxylate andtriphenylphosphine to give the phthalimidoethylpiperidine. Removal ofthe phthaloyl group, for example by treatment with methylhydrazine,gives the amine of formula (V).

R⁵CH₂-halides, acyl derivative R⁵COW and R⁵SO₂W or aldehydes R⁵CHO arecommercially available or are prepared conventionally. The aldehydes maybe prepared by partial reduction of the R⁵-ester with lithium aluminiumhydride or di-isobutylaluminium hydride or more preferably by reductionto the alcohol, with lithium aluminium hydride or sodium borohydride orlithium triethylborohydride (see Reductions by the Alumino- andBorohydrides in Organic Synthesis, 2nd ed., Wiley, N.Y., 1997; JOC,3197, 1984; Org. Synth. Coll., 102, 1990; 136, 1998; JOC, 4260, 1990;TL, 995, 1988; JOC, 1721, 1999; Liebigs Ann./Recl., 2385, 1997; JOC,5486, 1987), followed by oxidation to the aldehyde with manganese (II)dioxide, or by a ‘Swern’ procedure (oxalyl chloride/DMSO), or by usingpotassium dichromate (PDC). The aldehydes may also be prepared fromcarboxylic acids in two stages by conversion to a mixed carbonate forexample by reaction with isobutyl chloroformate followed by reductionwith sodium borohydride (R. J. Alabaster et al., Synthesis, 598, 1989)to give the hydroxymethyl substituted heteroaromatic or aromatic andthen oxidation with a standard oxidising agent such as pyridiniumdichromate or manganese (II) dioxide. Acyl derivative R⁵COW may beprepared by activation of the R⁵-ester. R⁵CH₂-halides such as bromidesmay be prepared from the alcohol R⁵CH₂OH by reaction with phosphorustribromide in DCM/triethylamine.

Alternatively the aldehyde R⁵CHO and sulphonic acid derivative R⁵SO₂Wmay be generated by treatment of the R⁵H heterocycle with suitablereagents. For example benzoxazinones, or more preferably theirN-methylated derivatives can be formylated with hexamine in eithertrifluoroacetic acid or methanesulfonic acid, in a modified Duffprocedure [O. I. Petrov et al. Collect. Czech. Chem. Commun. 62, 494-497(1997)]. 4-Methyl-4H-benzo[1,4]oxazin-3-one may also be formylated usingdichloromethyl methyl ether and aluminium chloride giving exclusivelythe 6-formyl derivative. Reaction of a R⁵H heterocycle withchlorosulphonic acid gives the sulphonic acid derivative (by methodsanalogous to Techer et. al., C. R. Hebd. Seances Acad. Sci. Ser. C; 270,1601, 1970).

The aldehyde R⁵CHO may be generated by conversion of an R⁵halogen orR⁵trifluoromethane sulphonyloxy derivative into an olefin withsubsequent oxidative cleavage by standard methods. For example, reactionof a bromo derivative under palladium catalysis withtrans-2-phenylboronic acid under palladium catalysis affords a styrenederivative which upon ozonolysis affords the required R⁵CHO (Stephenson,G. R., Adv. Asymmetric Synth. (1996), 275-298. Publisher: Chapman &Hall, London).

R⁵H heterocycles are commercially available or may be prepared byconventional methods. For example where a benzoxazinone is required, anitrophenol may be alkylated with for example ethyl bromoacetate and theresulting nitro ester reduced with Fe in acetic acid (alternativelyZn/AcOH/HCl or H₂/Pd/C or H₂/Raney Ni). The resulting amine may undergospontaneous cyclisation to the required benzoxazinone, or cyclisationmay be induced by heating in acetic acid. Alternatively a nitrophenolmay be reduced to the aminophenol, which is reacted with chloroacetylchloride [method of X. Huang and C. Chan, Synthesis 851 (1994)] or ethylbromoacetate in DMSO [method of Z. Moussavi et al. Eur. J. Med. Chim.Ther. 24, 55-60 (1989)]. The same general routes can be applied toprepare benzothiazinones [See for example F. Eiden and F. Meinel, Arch.Pharm. 312, 302-312 (1979), H. Fenner and R Grauert Liebigs. Ann. Chem.193-313 (1978)]. A variety of routes are available to prepare azaanalogues of benzothiazinones via the key corresponding aldehydes. Forinstance, 2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7-carbaldehydemay be accessed from 5-fluoro-2-picoline (E. J. Blanz, F. A. French, J.R. DoAmaral and D. A. French, J. Med. Chem. 1970, 13, 1124-1130) byconstructing the thiazinone ring onto the pyridyl ring thenfunctionalising the methyl substituent. The dioxin analogue of this azasubstitution pattern,2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde is accessiblefrom Kojic acid by aminolysis from pyrone to pyridone then annelatingthe dioxin ring. Other aza substitution patterns withpyridothiazin-3-one, pyridooxazin-3-one, and pyridodioxin ring systemsare also accessible. Ortho-aminothiophenols may be conveniently preparedand reacted as their zinc complexes [see for example V. Taneja et alChem. Ind. 187 (1984)]. Benzoxazolones may be prepared from thecorresponding aminophenol by reaction with carbonyl diimidazole,phosgene or triphosgene. Reaction of benzoxazolones with diphosphoruspentasulfide affords the corresponding 2-thione. Thiazines and oxazinescan be prepared by reduction of the corresponding thiazinone oroxazinone with a reducing agent such as lithium aluminium hydride.

The amines R^(2′)R^(4′)NH are available commercially or preparedconventionally. For example amines R⁵CH₂NH₂ may be prepared from abromomethyl derivative by reaction with sodium azide indimethylformamide (DMF), followed by hydrogenation of the azidomethylderivative over palladium-carbon. An alternative method is to usepotassium phthalimide/DMF to give the phthalimidomethyl derivative,followed by reaction with hydrazine in DCM to liberate the primaryamine.

Conversions of R^(1a′), R^(1′), R^(2′), R^(3′) and R^(4′) maybe carriedout on the intermediates of formulae (IV), and (V) prior to theirreaction to produce compounds of formula (I) in the same way asdescribed above for conversions after their reaction.

Further details for the preparation of compounds of formula (I) arefound in the examples.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds of formula (I). Libraries ofcompounds of formula (I) may be prepared by a combinatorial “split andmix” approach or by multiple parallel synthesis using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I) orpharmaceutically acceptable derivatives thereof.

Novel intermediates of formulae (IV) and (V) are also part of thisinvention.

The antibacterial compounds according to the invention may be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other antibacterials.

The pharmaceutical compositions of the invention include those in a formadapted for oral, topical or parenteral use and may be used for thetreatment of bacterial infection in mammals including humans.

The composition may be formulated for administration by any route. Thecompositions may be in the form of tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

No toxicological effects are indicated when a compound of formula (I) ora pharmaceutically acceptable derivative thereof is administered in theabove-mentioned dosage range.

The compound of formula (I) may be the sole therapeutic agent in thecompositions of the invention or a combination with otherantibacterials. If the other antibacterial is a β-lactam then aβ-lactamase inhibitor may also be employed.

Compounds of formula (I) are active against a wide range of organismsincluding both Gram-negative and Gram-positive organisms.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following examples illustrate the preparation of certain compoundsof formula (I) and the activity of certain compounds of formula (I)against various bacterial organisms.

Abbreviations in the Examples:

-   RT=room temperature-   ES=Electrospray mass spec.-   LCMS=Liquid chromatography mass spec.-   APCI+=Atmospheric pressure chemical ionisation mass spec

EXAMPLES Example 14-2-{4-[(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-piperidin-1-yl}-ethyl)-quinoline-6-carbonitriledihydrochloride

(a)4-[(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemethyl)-amino]-benzonitrile

A mixture of 4-amino-benzonitrile (12.5 g, 0.106 mol),2,2-dimethyl-[1,3]dioxane-4,6-dione (18.3 g, 0.127 mol) andtrimethylorthoformate (16 ml) in ethanol (100 ml) was refluxed for 3hours. After cooling the solid was filtered off, washed with ethanol andair dried. The product was obtained as an off-white solid (27.9 g, 97%).

MS (+ve ion electrospray) m/z 273 (MH+).

(b) 4-Oxo-1,4-dihydro-quinoline-6-carbonitrile

Intermediate (a) (27.5 g, 0.101 mol) was slowly added over five minutesto refluxing Dowtherm A (200 ml). After an additional five minutes atreflux, the mixture was allow to cool to room temperature then ether(200 ml) was added. The product was filtered off, thoroughly washed withether then air dried to afford the product as a gold coloured solid(16.2 g, 94%).

MS (+ve ion electrospray) m/z 171 (MH+).

(c) 4-Bromo-quinoline-6-carbonitrile

To a solution of (b) (12 g, 70.5 mmol) in DMF (75 ml) was added dropwisephosphorous tribromide (8 ml, 84.6 mmol) over five minutes (slightlyexothermic). The reaction was allowed to cool to room temperature andwas then diluted with ice water (100 ml) and stirred 1 hour then dilutedwith additional water (300 ml). The product was filtered off, washedwith water and air dried to provide 14.3 g of product (87%).

MS (+ve ion electrospray) m/z 233 (MH+).

(d) 4-Vinyl-quinoline-6-carbonitrile

To a solution of (c) (1 g, 4.3 mmol) and vinyltributyltin (1.5 mL, 5.17mmol) in degassed toluene (20 ml) was added tetrakis(triphenylphosphine)palladium (0) (245 mg, 5 mol %) and the mixture was refluxed under argonfor 2 hours. Evaporation and flash silica chromatography eluting withchloroform afforded the product as a pale yellow solid (500 mg, 64%).

MS (+ve ion electrospray) m/z 181 (MH+).

(e) {1-[2-(6-Cyano-quinolin-4-yl)-ethyl]-piperidin-4-yl}-carbamic acidtert-butyl ester

A mixture of (d) (150 mg, 0.8 mmol), piperidin-4-yl-carbamic acidtert-butyl ester (166 mg, 0.8 mmol) and chloroform (0.5 ml) were heatedat 50° C. in a loosely capped vial for 6 hours. The product was purifiedby flash silica chromatography eluting with a 0-2% methanol inchloroform gradient affording the product as a foam (304 mg, 96%).

MS (+ve ion electrospray) m/z 381 (MH+).

(f) 2-Bromo-5-hydroxy-6-nitropyridine

3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol(400 ml) and a solution of 25% sodium methoxide in methanol (33 ml, 0.13mol) was added at room temperature. The mixture was stirred for 30minutes, then cooled to 0° C., and bromine (7.2 ml, 0.14 mol) was addedslowly. The reaction was then stirred at 0° C. for 30 minutes, then wasquenched with glacial AcOH (2.5 ml). The solvent was removed in vacuo toafford material (30 g, 96%), which was used without furtherpurification.

MS (+ve ion electrospray) m/z 219 (MH+).

(g) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate

The hydroxypyridine (f) (30 g, 0.14 mol) was suspended in acetone (200ml), and potassium carbonate (39 g, 0.28 mol) was added, followed byethyl bromoacetate (15.7 ml, 0.14 mmol). The reaction was heated atreflux for 10 hours, then was cooled to room temperature and dilutedwith Et₂O. The precipitate was removed by suction filtration, and thefiltrate was concentrated in vacuo to afford material (38 g, 89%), whichwas used without further purification.

MS (+ve ion electrospray) m/z 305 (MH+).

(h) 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one

The nitropyridine (g) (38 g, 0.125 mol) was dissolved in glacial AcOH(150 ml), and iron powder (20 g, 0.36 mole) was added. The mixture wasmechanically stirred and heated at 90° C. for 5 hours, then was cooledto room temperature and diluted with EtOAc (300 ml). The mixture wasfiltered through a pad of silica gel and the filtrate was concentratedin vacuo and the residue recrystallized from MeOH (15 g, 52%).

MS (+ve ion electrospray) m/z 229 (MH+).

(i) 6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

The bromopyridine (h) (6.0 g, 26.3 mmol) and trans-2-phenylvinylboronicacid (3.9 g, 26.3 mmol) were dissolved in 1,4-dioxane (150 ml) and thesolution was degassed with argon. (Ph₃P)₄Pd (230 mg, 0.2 mmol) wasadded, followed by a solution of potassium carbonate (6.9 g, 50 mmol) inwater (20 ml). The reaction was heated at reflux under argon overnight,then was cooled to room temperature and diluted with EtOAc (200 ml). Thesolution was washed sequentially with water and brine, dried (Na₂SO₄),and concentrated in vacuo. The solid residue was purified by flashchromatography on silica gel (5-10% EtOAc/CHCl₃) to afford a solid (2.5g, 38%).

MS (+ve ion electrospray) m/z 253 (MH+).

(j) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

The pyridine (i) (1.2 g, 4.8 mmol) was dissolved in dichloromethane (200ml) and the solution was cooled to −78° C. Ozone was bubbled through thesolution with stirring until a pale blue color appeared, then the excessozone was removed by bubbling oxygen through the solution for 15 min.Dimethylsulfide (1.76 ml, 24 mmol) was added to the solution, and thereaction was stirred at −78° C. for 3 hours, then at room temperatureovernight. The solvent was removed in vacuo, and the residue wastriturated with Et₂O (50 ml). The collected solid was washed withadditional Et₂O and dried to afford a solid (700 mg, 82%).

MS (+ve ion electrospray) m/z 179 (MH+).

(k) Title Compound:

A solution of (e) (119 mg, 0.31 mmol) in dichloromethane (2 ml) wastreated with trifluoroacetic acid (2 ml) dropwise and then stirred atroom temperature for 1 hour. Evaporation to dryness gave the crudetrifluoroacetate salt of the amine which was redissolved indichloromethane (3 ml) and methanol (1 ml). Aldehyde (j) (55 mg, 0.31mmol) and triethylamine (0.17 ml) were added and the mixture was stirredat room temperature overnight. Sodium borohydride (38 mg, 1 mmol) wasadded and the reaction was allowed to stir for 1 hour. Dilution withchloroform, washing with saturated aqueous sodium bicarbonate, dryingand evaporation gave an oil. Chromatography on silica gel eluting with2-10% methanol in chloroform afforded the free base of the titlecompound as an oil. Redissolving in ethylacetate-methanol and treatmentwith 2 equivalents of HCl precipitated the dihydrochloride salt of theproduct which was filtered, washed with ether and dried (45 mg, 26%)

¹H NMR (MeOH-d4, 400 MHz): 8.92 (d, 1H), 8.48 (d, 1H), 8.20 (d, 1H),7.84 (dd, 1H), 7.40 (d, 1H), 7.20 (d, 1H), 6.94 (d, 1H), 4.65 (s, 2H),3.85 (s, 2H), 3.28 (m, 2H), 3.02 (m, 2H), 2.72 (m, 2H), 2.56 (m, 1H),2.15 (m, 2H), 1.96 (m, 2H), 1.54 (m, 2H).

MS (+ve ion electrospray) m/z 443 (MH+).

Example 26-({(3R,4S)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)4H-pyrido[3,2-b][1,4]thiazin-3-onedihydrochloride and6-({(3S,4R)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)4H-pyrido[3,2-b][1,4]thiazin-3-onedihydrochloride

(a) 8-Benzyoxyquinolin-2-ol

To a stirred solution of 2,8-quinolinediol (30.84 mmol, 4.97 g; Fluka)and DBU (40.2 mmol, 6 mL) in isopropyl alcohol (60 mL) was added benzylbromide (30.84 mmol, 3.7 mL). The solution was heated at refluxovernight. The reaction mixture was allowed to cool and thenconcentrated in vacuo. The resulting residue was diluted with CH₂Cl₂ andwashed with 0.5 N NaOH, 10% HCl and water and dried over Na₂SO₄.Concentration provided 6 g (77%) of the tan solid, which was usedwithout further purification. LC/MS: (ES) m/z 252 (M+H)⁺.

(b) 8-Benzyloxy-2-methoxyquinoline

8-Benzyloxyquinolin-2-ol (a) (6 g, 23.9 mmol) was added to POCl₃ (45 mL)and heated with stirring at 80° C. for 10 h. The reaction was allowed tocool to room temperature and the excess POCl₃ was decomposed by slowlypouring the mixture into water at 30° C. The product was then extractedinto toluene and the combined organic layers were washed with saturatedaq. NaHCO₃ and dried over MgSO₄. Concentration provided 6.9 g of acolorless oil, crude 2-chloro-8-benzyloxyquinoline, which was directlyused in the next reaction step. LC/MS: (ES) m/z 270 (M+H)⁺.

The crude 2-chloro-8-benzyloxyquinoline from above was dissolved intoluene (10 mL) and added to a stirred 25 wt % solution of NaOMe in MeOH(50 mL). The reaction solution was heated with stirring overnight at 70°C. After cooling to room temperature, the reaction solution was pouredonto ice and extracted with toluene. The combined organic extracts weredried (MgSO₄) and concentrated in vacuo to give a colorless oil (6.14 g,92%). The product was used without further purification.

LC/MS: (ES) m/z 266 (M+H)⁺.

(c) 1,1,1-Trifluoromethanesulfonic acid 2-methoxyquinolin-8-yl ester

8-Benzyloxy-2-methoxyquinoline (b) (6.14 g, 23 mmol) was dissolved inEtOH (50 mL) and treated with 10% Pd/C (600 mg). The reaction mixturewas hydrogenated under an H₂ atmosphere (20 psi) in a Parr shakerapparatus for 3.5 h. The reaction was filtered and concentrated to give3.8 g (96%) of a colorless oil.

LC/MS: (ES) m/z 176 (M+H)⁺.

The product from above (3.8 g, 22 mmol) was dissolved in DMF (40 mL) andtreated with triethylamine (3.6 mL, 25.8 mmol) andN-phenyltrifluoromethanesulfonimide (8.54 g, 23.9 mmol). The reactionmixture was heated with stirring at 40° C. for 8 h. Upon cooling to roomtemperature, aq. K₂CO₃ solution was added and the product was extractedinto CH₂Cl₂. The combined organic extracts were washed with water (5×75mL), dried (Na₂SO₄) and concentrated to give 6.8 g (100%) of triflate asa light tan crystalline solid, which was used directly in the nextreaction without additional purification. LC/MS: (ES) m/z 308 (M+H)⁺.

(d) 2-Bromo-1-(2-methoxy-quinolin-8-yl)-ethanone

The triflate (2c) in DMF, triethylamine, butyl vinyl ether, palladium(II) acetate and 1,3-bis(diphenylphosphino)propane is heated at 60° C.for 3 hours then evaporated and chromatographed on silica gel(dichloromethane). The product is dissolved in TBF and water and treatedwith N-bromosuccinimide for 1 hour, then evaporated and chromatographedon silica gel to give the ketone.

(e) (R)-2-Bromo-1-(2-methoxy-quinolin-8-yl)-ethanol

The ketone (2d) in toluene is treated with(+)-B-chlorodiisopinocamphenylborane ((+)-DIP-chloride) and stirredovernight, then diethanolamine is added and the mixture is stirred for 3hours, filtered and then evaporated. Chromatography on silica gel givesthe product.

(f) 2-Methoxy-8-(R)-oxiranyl-quinoline

The alcohol (e) in methanol is stirred with potassium carbonate for 1hour, then is evaporated and chromatographed on silica gel to give theproduct.

(g) (3R, 4S) and (3S,4R)-4-Amino-1-tert-butoxycarbonyl-3-fluoropiperidine

To a solution of the enantiomeric mixture ofcis-4-benzylamino-1-tert-butoxycarbonyl-3-fluoropiperidine (preparedaccording to the procedures of J. Med. Chem. 1999, 42, 2087-2104, 1.0 g,3.2 mmole) in EtOH (40 mL) was added 3 N HCl (2.5 L) and 10% Pd/C (50mg). The reaction was shaken under H₂ (40 psi) on a Parr apparatus for14 h, then was filtered through Celite®. The filtrate was concentratedunder reduced pressure, and the residue was purified by flashchromatography on silica gel (10% MeOH/CHCl₃) to afford the titlecompound (370 mg, 53%) as a white solid.

MS (ES) m/e 219 (M +H)⁺.

(h) (3R,4S) and(3S,4R)-4-Benzyloxycarbonylamino-3-fluoro-piperidine-1-carboxylic acidtert-butyl ester

The amine (2 g) (5.49 g) in dichloromethane (150 ml) containingtriethylamine (3.5 ml) was treated with benzyl chloroformate (4.0 ml)and stirred at room temperature for 5 hr. It was evaporated andchromatographed on silica gel to afford the product (4.27 g).

(i) ((3R,4S) and (3S,4R)-3-Fluoro-piperidin-4-yl)-carbamic acid benzylester

The carbamate (2 h) (4.27 g) was treated with trifluoroacetic acid (8ml) in dichloromethane (40 ml) at room temperature for 3 hr thenevaporated to dryness. The residue was basified with sodium carbonateand extracted with 10% methanol-dichloromethane. The solution was dried(sodium sulfate) and evaporated to give the product as a white solid(2.92 g).

(j) {(3R,4S) and(3S,4R)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-yl}-carbamicacid benzyl ester

A 1:1 mixture of oxirane (2f) and piperidine (2i) is heated at 85° C.for 3 hr and the product chromatographed on silica gel.

(k) (R)-2-((3R,4S) and(3S,4R)-4-Amino-3-fluoro-piperidin-1-yl)-1-(2-methoxy-quinolin-8-yl)-ethanol

The carbamate (2j) is hydrogenated in methanol at room temperature over10% palladium charcoal, filtered and evaporated to afford the product.

(1) Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of ethyl 2-mercaptoacetate (1.473 ml) in DMF (48 ml) wasice-cooled and treated with sodium hydride (540 mg of a 60% dispersionin oil). After 1 hour methyl 6-amino-5-bromopyridine-2-carboxylate (3 g)(T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was addedand the mixture stirred for 16 hours at room temperature. The solutionwas diluted with EtOAc (1 litre), washed with water (3×300 ml), driedand evaporated to about 10 ml. The white solid was filtered off andwashed with a little EtOAc to give the ester (0.95 g).

MS (APCI⁻) m/z 223 ([M−H]⁻, 100%)

(m) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid

A solution of ester (2l) (788 mg) in dioxan (120 ml)/water (30 ml) wastreated dropwise over 2 hours with 0.5 M NaOH solution (8 ml) andstirred overnight. After evaporation to approx. 3 ml, water (5 ml) wasadded and 2N HCl to pH4. The precipitated solid was filtered off, washedwith a small volume of water and dried under vacuum to give a solid (636mg).

MS (APCI⁻) m/z 209 ([M−H]⁻, 5%), 165([M−COOH]⁻, 100%)

(n) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

A solution of the carboxylic acid (2m) (500 mg) in THF (24 ml) withtriethylamine (0.396 ml) was cooled to −10° C. and isobutylchloroformate (0.339 ml) added. After 20 minutes the suspension wasfiltered through kieselguhr into an ice-cooled solution of sodiumborohydride (272 mg) in water (8 ml), the mixture stirred 30 minutes andthe pH reduced to 7 with dilute HCl. The solvent was evaporated and theresidue triturated under water. The product was filtered and dried undervacuum to give a white solid (346 mg).

MS (APCI⁻) m/z 195 ([M−H]⁻, 50%), 165(100%)

(o) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of the alcohol (2n) (330 mg) in dichloromethane (30 ml)/THF(30 ml) was treated with manganese dioxide (730 mg) and stirred at roomtemperature. Further manganese dioxide was added after 1 hour (730 mg)and 16 hours (300 mg). After a total of 20 hours the mixture wasfiltered through kieselguhr and the filtrate evaporated. The product wastriturated with EtOAc/hexane (1:1) and collected to give a solid (180mg).

MS (APCI⁻) m/z 195 ([M−H]⁻, 95%), 165 (100%)

(p) Title Compound

A mixture of the carboxaldehyde (2o) and amine (2k) (100 mg) inDMF/methanol/acetic acid with 3A molecular sieves is heated at 85° C.for 2 hours, cooled and is treated with an excess of sodiumcyanoborohydride. After stirring overnight, the mixture is diluted withchloroform (20 ml) and washed with aqueous Na₂CO₃. The organic fractionis dried and evaporated. Chromatography of the residue on silica gelgives the free base of the title compound. Treatment with 4M HCl indioxan, evaporation and trituration with ether affords the titlecompound

Example 36-({(3R,4R)-3-Hydroxy-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)4H-pyrido[3,2-b][1,4]thiazin-3-onedihydrochloride and6-({(3S,4S)-3-Hydroxy-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-onedihydrochloride

(a) tert-Butyl 3,6-dihydro-2H-pyridine-1-carboxylate

1,2,3,6-tetrahydropyridine (15.0 g, 180 mmole) was added to a 10%aqueous solution of Na₂CO₃ (50 ml) and the solution was cooled to 0° C.Di-tert-butyl dicarbonate (39.8 g, 182 mmole) was added in portions over15 min with vigorous stirring. The solution was stirred at 0° C. for 1hr and then warmed to room temperature and stirred for an additional 18hr. The reaction solution was partitioned between Et₂O and saturatedNaCl solution. The ether layer was dried over Na₂SO₄ and concentrated invacuo to give an oil (31.80 g, 96%), which needed no furtherpurification.

MS (ES) m/z 184 (M+H)⁺.

(b) tert-Butyl 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate

A solution of (3a) (15.0 g, 81.9 mmole) in CH₂Cl₂ (150 mL) was treatedwith a solution of meta-chloroperbenzoic acid (18.36 g, 106.4 mmole) inCH₂Cl₂ (300 mL) which was added over 30 minutes at 0° C. The solutionwas allowed to warm to room temperature and stirred for 18 hr. Thereaction solution was washed with 5% aqueous K₂CO₃ and saturated NaClsolution, then dried over Na₂SO₄ and concentrated in vacuo to yield anoff-white solid. This was flash chromatographed on silica gel (20%EtOAc/hexanes) to yield a white solid (12.80 g, 78%).

MS (ES) m/z 200 (M+H)⁺.

(c) tert-Butyl (±)-trans-4-benzylamino-3-hydroxypiperidine-1-carboxylate

The ester (3b) (13.24 g, 66.5 mmole) was combined with benzylamine(14.53 mL, 133 mmole) and stirred while heating at 115° C. The reactionwas allowed to stir for 8 hr at 115° C. and then allowed to cool toambient temperature. EtOAc was added and the organic layer was washedsequentially with H₂O and saturated NaCl solution. The organic layer wasdried over Na₂SO₄ and concentrated to yield a yellow solid (19.31 g,95%): LCMS: m/z 307 (M+H)⁺. This mixture of regioisomers waschromatographed (preparative HPLC) on Lichrosphere silica gel 60A; 12 u,100 mm ID×250 mm L; 70:30:0.5 hexanes:TBF:diethylamine; 500 ml/min; uvdetection 254 nm; 4.5 g mixture per injection. The products, tert-butyl(±)-trans-3-benzylamino-4-hydroxy-piperidine-1-carboxylate andtert-butyl (±)-trans-4-benzylamino-3-hydroxy-piperidine-1-carboxylate,as assigned by NMR, were obtained in a 3:1 ratio with retention times of8.4 min and 6.5 min, respectively.

(d) tert-Butyl (±)-trans-4-amino-3-hydroxypiperidine-1-carboxylate

A solution of the ester (3c) (0.5 g, 1.63 mmole) in EtOH (40 mL) wastreated with 10% palladium on carbon (catalytic) and hydrogenated in aParr bottle for 6 hr at 40 psi. The solution was filtered through a plugof Celite®, and the filter pad was washed with EtOH. The filtrate wasconcentrated to yield a yellow oil (0.35 g, 99%). No furtherpurification was required.

MS (ES) m/z 217 (M+H)⁺.

(e) tert-Butyl(±)-trans-3-Hydroxy-4-[3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)amino]piperidine-1-carboxylate

A solution of amine (3d) is heated at 85° C. for 2 hours with thecarboxaldehyde (2o) in DMF/methanol/acetic acid with 3A molecularsieves, cooled and is treated with an excess of sodium cyanoborohydride. After stirring overnight, the mixture is diluted with chloroform (20ml) and washed with aqueous Na₂CO₃. The organic fraction is dried andevaporated. Chromatography of the residue on silica gel gives theproduct

(f)(±)-trans-3-Hydroxy-4-[3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)amino]piperidine

A solution of (3e) in CH₂Cl₂ is treated with 4.0 N HCl/dioxane. Thesolution is allowed to stir for 30 min and then is concentrated in vacuoand dissolved in MeOH and treated with MP-Carbonate resin. The solutionis then filtered and evaporated to dryness.

(g) Title Compound

A 1:1 mixture of oxirane (2f) and piperidine (3f) is heated at 85° C.for 3 hr and then chromatographed on silica gel to provide the product

Example 46({(3R,4S)-1-[2-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-3-fluoro-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one

(a) 7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamine

A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (1 g, 6.6 mmol) intetrahydrofuran (15 ml) was cooled to 78 deg C. then treated with 1 dropof concentrated sulphuric acid followed by N-bromosuccinimide (1.2 g,6.6 mmol). The mixture was allowed to warm to room temperature over 1hour then evaporated. The residue was dissolved in ether, washed withwater then brine, dried and evaporated to afford an oil (1.4 g, 93%).

MS (+ve ion electrospray) m/z 231 (MH+).

(b)5-[(7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

A mixture of aniline (4a) (14.8 g, 64.3 mmol), triethyl orthoformate(12.7 mL, 77.2 mmol) and 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum'sacid) (11.1 g, 77.2 mmol) in ethanol (70 mL) was heated to reflux. After1 hour the mixture was allowed to cool to room temperature thenfiltered, washing with ethanol then ether, to afford a white solid (22.9g, 93%).

MS (+ve ion electrospray) m/z 385 (MH+).

(c) 6-Bromo-2,3-dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one

Enamine (4b) (22.9 g) was added portionwise to refluxing Dowtherm A (45mL) over 3 minutes. After a further 3 minutes at reflux the mixture wascooled to room temperature. Ethyl acetate/hexane (10 mL/20 mL) was addedand a black solid isolated by filtration. This residue was dissolved inhot methanol (400 mL) and filtered through Keiselguhr. Water (800 mL)was added and the mixture stored at 5° C. overnight. Filtration anddrying afforded a pale yellow solid (10.3 g, 61%).

MS (APCI⁻) m/z 281 [M−H]⁻

(d) 2,3-Dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one

A suspension of (4c) (3.4 g, 12 mmol) in water/dioxan (150 mL/80 mL) wastreated with 1M aqueous sodium hydroxide solution then hydrogenated over10% palladium on charcoal (1.5 g) for 20 hours. The mixture was filteredthen acidified with 5M aqueous hydrochloric acid. On concentrating to ca100 mL, a solid began to crystallise out. The mixture was stored at 5°C. overnight. Filtration and drying afforded a pale yellow solid (2.8 g,100%).

MS (APCI⁻) m/z 202 [M−H]⁻

(e) 10-Bromo-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

The quinolinone (4d) in dry DMF (8 mL) was cooled in ice and phosphorustribromide (0.7 mL) added drop-wise, and the mixture was stirred, withice-cooling for 30 minutes then allowed to warm to room temperature andstirred for a further 2 hours. It was cooled in ice and sodium carbonatesolution was added and the solid was collected, washed well with water,and dried in vacuo, to afford a pale yellow solid (1.65 g).

MS (ES) m/z 267 (M+H)⁺.

(f) 10-Vinyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

To a solution of (4e) (0.8 g) and vinyltributyltin (1.05 mL) in degassedtoluene (15 ml) was added tetrakis(triphenylphosphine) palladium (0)(173 mg) and the mixture was refluxed under argon for 2 days. Morevinyltributyltin (0.8 mL) and tetrakis(triphenylphosphine) palladium (0)(173 mg) were added and the reaction mixture was heated at 130° C. for afurther 18 hours. Evaporation and flash silica chromatography elutingwith hexane-DCM and ethyl acetate-DCM afforded the product as a yellowoil (500 mg, 64%).

MS (+ve ion electrospray) m/z 214 (MH+).

(g){(3R,4S)-1-[2-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-3-fluoro-piperidin-4-yl}-carbamicacid benzyl ester

A mixture of (4f) (373 mg), piperidine (2i) (440 mg) and chloroform (3ml) were heated at 120° C. in a loosely capped vial for 18 hours, underargon. The product was purified by flash silica chromatography elutingwith a 0-5% methanol in dichloromethane gradient affording the productas a foam (480 mg, 59%).

MS (+ve ion electrospray) m/z 466 (MH+).

(h)(3R,4S)-1-[2-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-3-fluoro-piperidin-4-ylamine

The carbamate (4g) was hydrogenated in methanol at room temperature over10% palladium charcoal, filtered and evaporated to afford the product(240 mg, 71%)

MS (+ve ion electrospray) m/z 332 (MH+).

(i) Title Compound

A mixture of aldehyde (2o) (142 mg) and amine (4h) (240 mg) inDMF/methane/acetic acid with 3A molecular sieves was heated at 85° C.for 3 hours, cooled and was treated with an excess of sodiumcyanoborohydride. After stirring overnight, the mixture was diluted withchloroform (20 ml) and washed with aqueous sodium bicarbonate. Theorganic fraction was dried and evaporated. Chromatography of the residueon silica gel gave the free base of the title compound (9 mg).

¹H NMR δH (DMSO, 400 MHz), 1.29-1.32 (2H, m), 1.66-1.68 (2H, d), 2.07(2H, t), 2.56 (2H, m), 2.89 (2H, m), 3.20 (3H, m), 3.95 (3H, s), 6.76(1H, d), 7.20 (1H, s), 7.35 (1H, d), 8.15 (1H, d), 8.72 (1H, s)

MS (+ve ion electrospray) m/z 510 (MH+).

Example 56-{[(1-{(2R/S)-2-hydroxy-2-[3-(methyloxy)-5-quinoxalinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride

(a) 2-Nitro-6-triisopropylsilanyloxy-phenylamine

A solution of 2-amino-3-nitro-phenol (42.9 g, 278 mmol) and imidazole(28.4 g, 417 mmol) in tetrahydrofuran (750 ml) was treated withchloro-triisopropyl-silane (62.3 g, 323 mmol). After 18 hours themixture was filtered, diluted with ethyl acetate, washed with water,dried and evaporated to give an oil (91 g).

MS (+ve ion electrospray) m/z 311 (MH+).

(b) 3-Triisopropylsilanyloxy-benzene-1,2-diamine

A solution of (5a) (91 g) in ethanol (500 ml) was hydrogenated over 10%palladium on charcoal (8.5 g) for 3 days then filtered and evaporated togive an oil (80.7 g).

MS (+ve ion electrospray) m/z 281 (MH+).

(c) 8-Triisopropylsilanyloxy-1H-quinoxalin-2-one

A solution of (5b) (80.7 g) in ethanol (1 litre) was treated with a 50%solution of ethyl glyoxalate in toluene (60 ml, 294 mmol) and heated toreflux for 2 hours. The mixture was left at room temperature overnightand filtered affording 5-triisopropylsilanyloxy-1H-quinoxalin-2-one. Thefiltrate was evaporated and the residue chromatographed eluting with a0-3% gradient of methanol in dichloromethane affording8-triisopropylsilanyloxy-1H-quinoxalin-2-one as a white solid (14.9 g).

MS (+ve ion electrospray) m/z 319 (MH+).

(d) 2-Methoxy-8-triisopropylsilanyloxy-quinoxaline

A solution of (5c) (2.0 g, 6.2 mmol) indichloromethane/methanol/acetonitrile (40 ml/4 ml/40 ml) was treatedwith triethylamine (1.1 ml, 8 mmol) then a solution of(trimethylsilyl)diazomethane in hexane (2M; 4 ml, 8 mmol). The mixturewas stirred overnight then evaporated. The residue was chromatographedon silica eluting with dichloromethane affording an oil (1.0 g, 48%).

MS (+ve ion electrospray) m/z 333 (MH+).

(e) 3-Methoxy-quinoxalin-5-ol

A solution of (5d) (6.95 g, 21 mmol) in tetrahydrofuran/methanol (280ml/140 ml) was treated with caesium fluoride (4.73 g, 31.4 mmol) andstirred for 18 hours. The mixture was evaporated and the residuepartitioned between diethyl ether and dilute aqueous hydrochloric acid.The aqueous phase was further extracted with diethyl ether and thecombined extracts dried and evaporated to give an oil (4.2 g).

MS (+ve ion electrospray) m/z 177 (MH+).

(f) 1,1,1-Trifluoro-methanesulfonic acid 3-methoxy-quinoxalin-5-yl ester

A solution of (5e) (4.23 g, 21 mmol) in dichloromethane (35 ml) wastreated with triethylamine (4.5 ml, 32.1 mmol) thenN-phenyltrifluoromethanesulfonimide (11.4 g, 32 mmol) was added. Themixture was stirred overnight then washed with saturated aqueous sodiumcarbonate solution. The aqueous phase was further extracted withdichloromethane and the combined organic extracts were dried andevaporated. The residue was chromatographed on silica eluting with 50%hexane in dichloromethane and then dichloromethane, affording an oil(5.6 g, 87%).

MS (+ve ion electrospray) m/z 309 (MH+).

(g) 1-(3-methoxyquinoxalin-5-yl)ethanone

To a solution of triflate (5f) (7.4 g, 24.2 mmol) and1,3-bis(diphenylphosphino) propane (1.0 g, 0.24 mmol) in DMF (100 mL),under argon, were added palladium acetate (0.55 g, 0.24 mmol),triethylamine (6.73 mL, 48.6 mmol) and butyl vinyl ether (12.6 mL, 97.0mmol). The reaction mixture was heated at 70° C. for 8.5 hours. DMF wasremoved in vacuo and the residue was chromatographed on a silica gelcolumn eluting with 0-2% methanol in dichloromethane, affording theproduct as an oil (4.22 g, 68%)

MS (+ve ion electrospray) m/z 203 (MH+).

(h) 2,2-dibromo-1-[3-(methyloxy)-5-quinoxalinyl]ethanone

To a solution of ethanone (5g) (3.95 g, 19.5 mmol) in dioxan (40 mL), asuspension of bromine (1.14 mL, 22 mmol) in dioxan (40 mL) was added atroom temperature. The reaction mixture was stirred at room temperatureover 2 nights. The reaction mixture was basified by addition of anaqueous solution of sodium bicarbonate and extracted several times withdichloromethane. The combined organic extracts were washed with anaqueous solution of sodium sulfite, dried over magnesium sulfate andevaporated in vacuo. The residue was chromatographed on a silica gelcolumn eluting with 0-2% methanol in dichloromethane, affording theproduct as an oil (4.19 g, 59%).

MS (+ve ion electrospray) m/z 361 (MH+).

(i) 2-bromo-1-[3-(methyloxy)-5-quinoxalinyl]ethanone

To a solution of ethanone (5h) (4.19 g, 11.64 mmol) in THF (20 mL),cooled to 0° C., a mixture of diethyl hydrogen phosphite (1.56 mL, 12mmol), and triethylamine (1.68 mL, 12 mmol) in THF (10 mL) was addedslowly. The reaction mixture was allowed to reach room temperatureovernight. More diethyl hydrogen phosphite (2×0.08 mL), andtriethylamine (2×0.08 mL) were added and the reaction mixture wasevaporated in vacuo after 7.5 hours. Water was added to the residue. Asolid precipitated out, was washed with water and dried to afford theproduct as a white powder (2.68 g, 82%).

MS (+ve ion electrospray) m/z 282 (MH+).

(j) (+/−) 2-(methyloxy)-8-(2-oxiranyl)quinoxaline

The ketone (5i) (2.83 g, 10.07 mmol) was partially dissolved in methanol(50 mL). The reaction mixture was cooled down to 0° C. before sodiumborohydride (0.78 g, 20.6 mmol) was added portionwise. The reactionmixture was stirred at 0° C. for 1 hour. More sodium borohydride wasadded (0.14 g) and the new reaction mixture was stirred for a further 20minutes. Cesium carbonate (7.5 g, 20 mmol) was then added and thereaction mixture was allowed to reach room temperature. Stirring at roomtemperature was continued for 3 days until total conversion to epoxide.The mixture was diluted with water and extracted several times withdichloromethane. The combined organic extracts were washed with water,dried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed on a silica gel column eluting with 0-1% methanol indichloromethane, affording the product as a white solid (0.83 g, 41%)

MS (+ve ion electrospray) m/z 203 (MH+).

(k) (+/−) 1,1-dimethylethyl(1-{2-hydroxy-2-[3-(methyloxy)-5-quinoxalinyl]ethyl}-4-piperidinyl)carbamate

A mixture of oxirane (5j) (0.83 g, 4.1 mmol) and 1,1-dimethylethyl4-piperidinylcarbamate (1.23 g, 6.16 mmol) in DMF (1 mL) was heated at90° C. for 4 hours then cooled down to room temperature. The reactionmixture was diluted with ethyl acetate and washed with water. Theaqueous layer was extracted a second time with ethyl acetate. Thecombined organic extracts were dried over magnesium sulfate andevaporated in vacuo. The residue was chromatographed on a silica gelcolumn eluting with 2-5% methanol in dichloromethane, affording theproduct as a white solid (1.46 g, 88%)

MS (+ve ion electrospray) m/z 403 (MH+).

(l) (+/−)2-(4-amino-1-piperidinyl)-1-[3-(methyloxy)-5-quinoxalinyl]ethanol

A solution of amine (5k) in dioxan (10 mL) was treated with 4.0NHCl/dioxan. The solution was allowed to stir at room temperature for 3.5hours. The reaction mixture was diluted with diethyl ether and filtered.The precipitate was washed with more diethyl ether and dried in vacuo.It was then recrystallised from methanol/dichloromethane. The crystalswere redissolved in a minimum amount of water and the solution wasbasified by addition of sodium bicarbonate. The solution was extractedseveral times with 10% methanol in dichloromethane. The combined organicextracts were dried over magnesium sulfate, filtered and evaporated invacuo to afford the product as a solid (0.64 g, 57%)

MS (+ve ion electrospray) m/z 303 (MH+).

(m) Title Compound

A mixture of ethanol (5l) (30 mg, 0.1 mmol) and aldehyde (2o) (19 mg,0.1 mmol) in chloroform/methanol with 3A molecular sieves was heated atreflux for 5 hours, cooled and was treated with sodiumtriacetoxyborohydride (42 mg, 0.2 mmol). After stirring for 48 hours atroom temperature, the mixture was diluted with chloroform and washedwith aqueous sodium bicarbonate. The aqueous layer was extracted againwith methanol/dichloromethane. The combined organic fractions were driedand evaporated. Chromatography of the residue on silica gel eluting with5-10% methanol in dichloromethane gave the free base of the titlecompound (23 mg, 48%).

¹H NMR δH (CDCl₃, 250 MHz), 1.60-1.91 (2H, m), 2.00-2.16 (2H, m),2.15-2.20 (1H, m) 2.32-2.84 (6H, m), 3.47 (2H, s), 3.87 (2H, s), 4.05(3H, s), 5.78 (1H, m), 6.98 (1H, d), 7.55-7.61 (2H, m), 7.91-7.94 (2H,m), 8.48 (1 h, s)

MS (+ve ion electrospray) m/z 481 (MH+).

Treatment with 4M HCl in dioxan, evaporation and trituration with etherafforded the title compound.

The mixture of enantiomers was separated using Supercritical FluidChromatography (SFC) on Chiralpak AD stationary phase, eluting with 65%methanol (containing 0.5% isopropylamine) in liquid carbon dioxide. Thisprovided the faster-running enantiomer (61 mg, Retention time=9.4minutes, alpha D=−91.5 degrees) then the slower-running enantiomer (68mg, Retention time=19.9 minutes, alpha D=+89.1 degrees).

Example 6(1R/S)-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]1-1-piperidinyl}-1-[3-(methyloxy)-5-quinoxalinyl]ethanoldihydrochloride

(a) 5-Benzyloxy-2-hydroxymethyl-1 H-pyridin-4-one

A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojicacid by the method of D. Erol, J. Med. Chem., 1994, 29, 893) (9.7 g, 40mmol), concentrated aqueous (880) ammonia (100 mL), and ethanol (20 mL)was heated to reflux overnight. The mixture was allowed to cool to roomtemperature then filtered. The resultant solid was washed with ether anddried in vacuo (5.9 g).

MS (APCI+) m/z 232 (MH+).

(b) (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol

A solution of (6a) (2 g, 8.7 mmol) in water (220 mL) containing sodiumhydroxide (17 mmol) was hydrogenated over 10% palladium on charcoal (1g) for 4 hours. The mixture was filtered and evaporated to give a whitesolid. This solid was dissolved in N,N-dimethylformamide (8 mL) thentreated with potassium carbonate (2.9 g) and 1,2-dibromoethane (0.6 mL,7 mmol). The mixture was heated at 85° C. overnight. The cooled mixturewas evaporated onto silica and chromatographed eluting with 10-30%methanol in ethyl acetate affording a white solid (250 mg, 21%).

MS (APCI+) m/z 168 (MH+).

(c) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde

A solution of (6b) (250 mg, 1.5 mmol) in dichloromethane (5 mL) wastreated with manganese dioxide (650 mg, 7.5 mmol). After 3 days themixture was filtered and evaporated affording a white solid (150 mg,61%).

MS (APCI+) m/z 166 (MH+).

(d) Title Compound

The free base was prepared as in Example 5 from amine (5l) (30 mg, 0.1mmol) and aldehyde (6c) (16 mg, 0.1 mmol).

¹H NMR δH (CDCl₃, 250 MHz), 1.43-1.61 (2H, m), 1.90-1.95 (2H, m), 2.15(1H, m), 2.37-2.94 (6H, m), 3.47 (2H, m), 3.81 (2H, s), 4.05 (3H, s),4.25-4.35 (4H, m), 5.74-5.79 (1H, m), 6.83 (1H, d), 7.55-7.61 (1H, m),7.91-7.94 (2H, m), 8.11 (1H, s), 8.48 (1H, s)

MS (+ve ion electrospray) m/z 452 (MH+).

Treatment with 4M HCl in dioxan, evaporation and trituration with etherafforded the title compound.

Example 7{1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-aminedihydrochloride

(a) 9-Chloro-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-10(7H)-one

The quinolone (4d) (5.05 g) in acetic acid (70 mL) was sonicated andwarmed until all had dissolved, and then it was treated withN-chlorosuccinimide (3.64 g) and the mixture was heated at 35° C. for 18hr, cooled and the solid collected and washed with acetic acid and driedin vacuo at 40° C. overnight, to give a white solid (1.65 g)

MS (ES) m/z 238/240 (M+H)⁺

(b) 10-Bromo-9-chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

The chloroquinolone (7a) in dry DMF (8 mL) was cooled in ice andphosphorus tribromide (0.7 mL) added drop-wise, and the mixture wasstirred, with ice-cooling for 30 minutes then allowed to warm to roomtemperature and stirred for a further 2 hours. It was cooled in ice andsodium carbonate solution was added and the solid was collected, washedwell with water, and dried in vacuo, to afford a pale yellow solid (1.65g).

MS (ES) m/z 301/303 (M+H)⁺.

(c) 9-Chloro-10-vinyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

The bromide (7b) (1.65 g) in DME (60 mL) under argon, was treated withtetrakis(triphenylphosphine)palladium(0) (0.32 g) and the mixturestirred at room temperature for 20 minutes. Anhydrous potassiumcarbonate (0.76 g), water (18 mL), and vinylborane:pyridine complex (seeF. Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) was added andthe mixture was heated at 100° C. for 2 hr. It was cooled, diluted withwater and extracted with ether, dried (magnesium sulfate) and evaporatedto dryness.

After work-up the product was chromatographed on silica gel, elutingwith (methanol-DCM) to afford a white solid (1.35 g).

MS (ES) m/z 248/250 (M+H)⁺.

(d){1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

A mixture of the vinyl-quinoline (7c) (680 mg) andpiperidin-4-yl-carbamic acid tert-butyl ester (815 mg) in DMF (0.9 mL)and tetramethylguanidine (5 drops) was heated at 100° C. for 18 hours.It was cooled, diluted with water and extracted with ethyl acetate,dried (magnesium sulfate) and evaporated to dryness. After work-up theproduct was chromatographed on silica gel, eluting with methanol-DCM toafford the desired product (0.82 g).

MS (ES) m/z 448 (M+H)⁺.

(e)1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-ylamine

The ester (7d) (0.82 g) in DCM (21 mL) was treated with TFA (21 mL) atroom temperature for 1 hr and evaporated. Water and sodium carbonatewere added and the solution was extracted with 10% methanol in ethylacetate, dried (magnesium sulfate) and evaporated to afford the product(0.53 g)

MS (ES) m/z 348 (M+H)⁺.

(f) Title Compound

The amine (7e) (0.53 g) and aldehyde (6c) (0.25 g) were dissolved in DMF(16 mL) and sodium triacetoxyborohydride (0.96 g) added and the solutionwas stirred overnight at room temperature. The reaction mixture wasquenched with 2N HCl, basified with sodium bicarbonate solution, andextracted with methanol-DCM to afford the free base of the titlecompound (0.25 g).

¹H NMR of the hydrochloride salt δH (d6-DMSO), 9.60 (2H, bs), 8.73 (1H,s), 8.20 (1H, s), 7.60 (1H, d), 7.45 (1H, d), 7.20 (1H, s), 4.50 (2H,m), 4.40 (4H, m), 4.32 (2H, m), 4.25 (2H, m), 3.90-3.70 (3H, m),3.40-3.10 (6H, m), 2.35-2.05 (4H, m),

MS (+ve ion electrospray) m/z 497 (MH+).

This material, as a solution in chloroform/methanol, was treated with anexcess of 1M HCl in ether and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (0.33 g).

Example 86-{[(1-{2-hydroxy-2-[2-(methyloxy)-8-quinolinyl]ethyl}4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

(a) 8-(1-Butoxy-vinyl)-2-methoxy-quinoline

Triflate (2c) (2.50 g, 8.14 mmol) was dissolved in DMF (25 mL). Aftersubsequent addition of butyl vinyl ether (4.21 mL, 32.55 mmol),palladium acetate (0.182 g, 0.81 mmol),1,3-bis(diphenylphosphino)propane (0.334 g, 0.81 mmol), andN,N-diisopropylethylamine (4.25 mL, 24.4 mmol), the reaction was heatedto 60° C. and stirred for 18 hours. The solution was then cooled toambient temperature and poured into a saturated NaHCO₃ solution. Thesolution was then extracted with EtOAc and washed with water (3×). Theorganic layer was then dried over Na₂SO₄, filtered, and the solventremoved under reduced pressure yielding an oil (2.80 g, >100% crude).¹

MS (+ve ion electrospray) m/z 258 (MH+).

(b) 2-Bromo-1-(2-methoxy-quinolin-8-yl)-ethanone

Vinyl (8a) (2.42 g, 9.42 mmol) was dissolved in THF (30 mL). Water (10mL) was added followed by N-bromosuccinimide (1.84 g, 10.36 mmol) atambient temperature. Immediately after addition, the color changed to alighter color. The reaction was stirred 10 minutes, filtered, and thesolvent removed under reduced pressure. This was chromatographed onsilica gel (CH₂Cl₂) to yield a yellow solid (1.25 g, 47%).

MS (+ve ion electrospray) m/z 280 (MH+).

(c){1-[2-(2-Methoxy-quinolin-8-yl)-2-oxo-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester.

Piperidin-4-yl-carbamic acid tert-butyl ester (0.356 g, 1.78 mmol) wasdissolved in dichloromethane (5.0 mL). Triethylamine (0.52 mL, 3.75mmol) was added and the solution stirred for 15 minutes at ambienttemperature. In a separate flask, bromomethyl (8b) (0.50 g, 1.78 mmol)was dissolved in dichloromethane (5.0 mL), and then added to theoriginal solution. The reaction mixture was allowed to stir at ambienttemperature for 18 hours. The solution was then diluted with ethylacetate and washed with water and saturated aqueous NaCl solution. Theorganic layer was then dried over Na₂SO₄, filtered, and the solventremoved under reduced pressure. The reaction yielded an off-white solid(0.501 g, 70%).

MS (+ve ion electrospray) m/z 400 (MH+).

(d){1-[2-Hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

The ketone (8c) (0.25 g, 0.627 mmol) was dissolved in tetrahydrofuran(10 mL) and the solution cooled to 0° C. NaBH₄ (0.024 g, 0.627 mmol) wasadded and the solution stirred at 0° C. for 2 hours and allowed to warmto ambient temperature overnight. The reaction was not complete, andthus another equivalent of NaBH₄ (0.024 g, 0.627 mmol) was added at 0°C. The solution was allowed to warm to ambient temperature and wasstirred for 3 more hours. The reaction was quenched with saturatedNaHCO₃ solution and diluted with ethyl acetate. The organic layer waswashed with water and saturated aqueous NaCl solution, dried overNa₂SO₄, filtered, and the solvent removed under reduced pressure.Purification by flash chromatography (silica gel, acetone/chloroform)yielded an off-white solid (0.162 g, 65%).

MS (+ve ion electrospray) m/z 402.4 (MH+).

(e) (4-Amino-piperidin-1-yl)-1-(2-methoxy-quinolin-8-yl)-ethanol

The carbamate (8d) (0.158 g, 0.394 mmol) was dissolved indichloromethane (2 mL). HCl in dioxane (1.0M:5 mL:5 mmol) was added andthe solution allowed to stir at room temperature for 18 hours. Thesolvent and excess HCl were removed under reduced pressure, yielding thedi-HCl salt (0.144 g, 98%) as a yellow solid.

MS (+ve ion electrospray) m/z 302.4 (MH+).

(f) Title Compound

Amine (8e) (0.144 g, 0.482 mmol) was added to aldehyde (1j) (0.094 g,0.530 mmol) dissolved in CH₂Cl₂ (3 mL) and MeOH (3 mL). NaHCO₃ (0.202 g,2.41 mmol) was then added and the solution allowed to stir at ambienttemperature for 17 hours. The solution was cooled to 0° C., excesssodium borohydride was added, and it was allowed to stir at ambienttemperature for 4 hours. The reaction mixture was poured into asaturated solution of NaHCO₃ and extracted with CHCl₃. (3×). The organiclayer was washed with water (2×) and brine, dried over Na₂SO₄, andevaporated to yield a yellow oil. This was chromatographed on silica gel(90:10:1 CHCl₃/MeOH/NH₄OH) to yield an off-white solid (0.012 g, 5%).

¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.39(t, 1H), 7.20 (d, 1H), 6.94 (d, 1H), 6.89 (d, 1H), 5.77 (dd, 1H), 4.63(s, 3H), 4.02 (s, 3H), 3.84 (s, 2H), 3.15 (d, 1H), 3.01 (d, 1H), 2.59(m, 2H), 2.38 (m, 1H), 2.21 (m, 1H); 1.97 (m, 2H); 1.58 (m, 2H).

MS (+ve ion electrospray) m/z 464.4 (MH+).

Example 96-[({1-[2-(4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-onedihydrochloride

(a) 1,1-dimethylethyl {1-[2-(4-quinolinyl)ethyl]-4-piperidinyl}carbamate

A solution of lepidine (2.5 mmol, 0.33 mL), 1,1-dimethylethyl4-piperidinylcarbamate (2.5 mmol, 0.500 g), 37% aqueous formaldehyde(2.6 mmol, 0.20 mL), and 6N HCl (2.6 mmol, 0.44 mL) in ethanol (1 mL)was heated to 50° C. overnight. The reaction mixture was cooled, dilutedwith chloroform, and washed with aqueous sodium bicarbonate solution.The aqueous layer was removed and the organic layer was washed withwater and brine, dried over magnesium sulfate, filtered, concentratedand chromatographed in 90:10:1 chloroform:methanol:ammonium hydroxide toafford the product as a white solid (278 mg, 31%).

LC-MS m/z 356 (MH+)

(b) 1-[2-(4-quinolinyl)ethyl]-4-piperidinamine trihydrochloride

1,1-dimethylethyl {1-[2-(4-quinolinyl)ethyl]-4-piperidinyl}carbamate(9a) (278 mg) was dissolved in chloroform and diluted with 4N HCl indioxane solution. After stirring two hours, the reaction mixture wasevaporated to dryness to afford the product as a solid (180 mg, 100%).

LC-MS m/z 286 (MH+)

(c) Title Compound

The trihydrochloride salt of amine (9b) (0.36 mmol, 180 mg) wasdissolved in 3 mL of 1:1 dichloromethane:methanol and treated withsodium bicarbonate (1.8 mmol, 152 mg) and carbaldehyde (2o) (0.36 mmol,70 mg) and stirred overnight. The suspension was treated with sodiumtriacetoxyborohydride (0.54 mmol, 114 mg) and stirred overnight. Theresulting reaction mixture was diluted with dichloromethane and pouredinto saturated aqueous sodium bicarbonate. The aqueous layer wasextracted with dichloromethane, and the combined organic layers werewashed with water and brine, dried over magnesium sulfate, filtered,concentrated, and chromatographed in 90:10:1chloroform:methanol:ammonium hydroxide. The final product was obtainedin 34% yield, 52 mg and converted to dihydrochloride salt.

δH (CDCl₃, 400 MHz), 8.81 (d, 1H), 8.11 (d, 1H), 8.09 (bs, 1H), 8.06(d,1H), 7.70 (t, 1H), 7.63-7.55 (m, 2H), 7.28 (s, 1H), 6.99 (d, 1H), 3.85(s, 2H), 3.43 (s, 2H), 3.28 (t, 2H), 3.04 (m, 2H), 2.73 (t, 2H), 2.56(m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.64-1.52 (m, 2H)

MS (ES) m/e 434 (M+H)⁺.

Example 104-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitriledihydrochloride (isomer E2)

(a) cis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylicacid benzyl ester.

Racemic cis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylicacid benzyl ester was prepared according to the procedure outlined byKim et al. [Syn. Comm. 2001, 31, 1081-1089] starting from3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester.

MS (ES) m/z 351 (M+H)⁺.

(b) cis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylicacid benzyl ester enantiomer 1 andcis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester enantiomer 2

71.0 g of the racemate (10a) was dissolved in methanol (710 mL) andresolved through multiple injections (1×8 g substrate injection; 5×10 gsubstrate injection; 1×7 g substrate injection; and 1×6 g substrateinjection) on a Chiralpak AD column (77×250 mm) eluting with 100%methanol at a flow rate of 280 mL/minute with UV detection at 254 nm.31.15 g ofcis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester fast running isomer (>99% ee, retention time 3.8 minutes(sharp), designated Isomer 1) and 26.75 g ofcis-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester slow running isomer (>99% ee, retention time 8.0 minutes(very broad), designated Isomer 2) were obtained.

(c) cis-(3-Hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester isomer2

10.0 g ofcis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester slow running Isomer 2 (10b), was dissolved in methanol (350mL) and was degassed. Pearlman's catalyst (palladium hydroxide oncarbon, 20wt % Pd (dry basis), ≦50% water, 500 mg) was added and themixture was purged with hydrogen and stirring continued under a balloonof hydrogen for 12 hours. The mixture was degassed with argon, filteredthrough a pad of Celite, and evaporated to dryness to afford 6.2 g(100%) of a white solid.

MS (ES) m/z 217 (M+H)⁺.

(d) 1,1-dimethylethyl{(3R,4S)-1-[2-(6-cyano-4-quinolinyl)ethyl]-3-hydroxy-4-piperidinyl}carbamate

A mixture of the vinyl-quinoline (1d) and piperidine (10c) was treatedas in example (7d) to afford the desired product in 86% yield.

MS (ES) m/z 397 (M+H)⁺.

(e)4-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-6-quinolinecarbonitriledihydrochloride

The carbamate (10d) was dissolved in dichloromethane. 4M HCl in dioxanewas added and the solution allowed to stir at room temperature for 18hours. The solvent and excess HCl were removed under reduced pressure,yielding the di-HCl salt as a yellow solid.

MS (+ve ion electrospray) m/z 297 (MH+).

(f) Title Compound

The dihydrochloride salt (10e) (1.4 mmol, 650 mg) was dissolved in 3 mLmethanol and diluted with 9 mL dichloromethane. The solution was treatedwith triethylamine (7.1 mmol, 0.99 mL) and aldehyde (1j) (1.4 mmol, 253mg) and stirred overnight. The resulting solution was treated withsodium borohydride (1.4 mmol, 54 mg) and stirred two hours. The reactionmixture was diluted with chloroform and poured into saturated aqueoussodium bicarbonate solution. The aqueous layer was extracted withchloroform, and the combined organic layers were washed with brine,dried over magnesium sulfate, filtered, concentrated, andchromatographed in 90:10:1 chloroform:methanol:ammonium hydroxide toafford the product a solid (394 mg, 60%).

δH (DMSO, 400 MHz), 8.94 (d, 1H), 8.81 (d, 1H), 8.15 (d, 1H), 8.05 (d,1H), 7.58 (t, 1H), 7.30 (d, 1H), 7.02 (d, 1H), 4.61 (s, 2H), 4.43 (bs,1H), 3.70 (m, 3H), 3.29 (t, 2H), 2.66 (t, 3H), 2.60 (bs, 1H), 2.39 (m,1H), 2.28 (m, 1H), 2.00 (m, 1H), 1.66 (m, 1H), 1.52 (m, 1H)

MS (+ve ion electrospray) m/z 459 (MH+).

This material was converted to the dihydrochloride salt by the procedureof example (2p)

Example 114-[2-(3-hydroxy-4-{([(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitriledihydrochloride (E2 isomer)

(a) Title Compound

Dihydrochloride (10e) (1.4 mmol, 650 mg) was dissolved in 3 mL methanoland diluted with 9 mL dichloromethane. The solution was treated withtriethylamine (7.1 mmol, 0.99 mL) and aldehyde (2o) (1.4 mmol, 345 mg,at 80% purity) and stirred overnight. The resulting solution was treatedwith sodium borohydride (1.4 mmol, 54 mg) and stirred two hours. Thereaction mixture was diluted with chloroform and poured into saturatedaqueous sodium bicarbonate solution. The aqueous layer was extractedwith chloroform, and the combined organic layers were washed with brine,dried over magnesium sulfate, filtered, concentrated, andchromatographed in 90:10:1 chloroform:methanol:ammonium hydroxide toafford the product as a solid (405 mg, 60%).

δH (DMSO, 400 MHz), 10.91 (bs, 1H), 8.94 (d, 1H), 8.81 (d, 1H), 8.15 (d,1H), 8.04 (d, 1H), 7.73 (d, 1H), 7.58 (d, 1H), 7.10 (d, 1H), 4.43 (bs,1H), 3.72 (m, 3H), 3.53 (s, 1H), 3.28 (t, 2H), 3.17 (d, 1H), 2.66 (t,1H), 2.60 (bs, 1H), 2.39 (m, 1H), 2.27 (m, 1H), 2.06 (m, 1H), 1.66 (m,1H), 1.52 (m, 1H)

MS (+ve ion electrospray) m/z 475 (MH+).

This material was converted to the dihydrochloride salt by the procedureof example (2p)

Example 124-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile(E1 isomer)

(a) Title Compound

Carbonitrile dihydrochloride (10e) (492 mg, 1.48 mmole), aldehyde (1j)(264 mg, 1.48 mmole) and triethylamine(1.03 mL, 7.42 mmole) werecombined in a 1:1 mixture of dichloromethane and methanol (20 mL), andthe mixture was stirred for 3 hours. Sodium borohydride (56 mg, 1.48mmole) were added, and the reaction was stirred at room temperature for30 minutes. The solution was diluted with chloroform, then washed withsaturated aqueous sodium bicarbonate solution and brine. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to yield anoff-white solid. This was flash chromatographed on silica gel (90:10:1CHCl₃/MeOH/NH₄OH) to yield the title compound (450 mg, 57%) as a whitesolid.

¹H NMR (400 MHz, DMSO) δ 8.96 (d, 1H), 8.79 (s, 1H), 8.31 (s, 1H), 8.17(d, 1H), 8.08 (d, 1H), 7.70 (d, 1H), 7.55 (s, 1H), 7.01 (d, 1H), 4.60(s, 2H), 4.45 (m, 1H), 3.76-3.80 (m, 3H), 3.24-3.37 (m, 2H), 2.59-2.79(m, 4H), 2.40-2.50 (m, 1H), 2.20-2.35 (m, 1H), 1.65-1.78 (m, 1H),1.42-1.60 (m, 1H), 1.00-1.13 (m, 2H)

MS (ES) m/e 459.5 (M+H)⁺.

This material was converted to the dihydrochloride salt by the procedureof example (2p)

Example 134-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile(E1 isomer)

(a) Title Compound

Carbonitrile dihydrochloride (10e) (492 mg, 1.48 mmole), aldehyde (2o)(287 mg, 1.48 mmole) and triethylamine(1.03 mL, 7.42 mmole) werecombined in a 1:1 mixture of dichloromethane and methanol (20 mL), andthe mixture was stirred for 3 hours. Sodium borohydride (56 mg, 1.48mmole) were added, and the reaction was stirred at room temperature for30 minutes. The reaction was diluted with chloroform, then washed withsaturated aqueous sodium bicarbonate solution and brine. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to yield anoff-white solid. This was flash chromatographed on silica gel (90:10:1CHCl₃/MeOH/NH₄OH) to yield the title compound (230 mg, 28%) as a whitesolid.

¹H NMR (400 MHz, DMSO)δ10.91 (s, 1H), 8.95 (d, 1H), 8.81 (s, 1H), 8.32(s, 1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.74 (d, 1H), 7.59 (s, 1H), 7.10(d, 1H), 4.45 (m, 1H), 3.70-3.78 (s, 3H), 3.51 (s, 2H), 3.28-3.34 (m,2H), 2.66-2.79 (m, 4H), 2.42-2.50 (m, 1H), 2.25-2.35 (m, 1H), 1.68-1.80(m, 1H), 1.43-1.60 (m, 1H), 1.08-1.13 (m, 2H)

MS (ES) m/e 475.5 (M+H)⁺.

This material was converted to the dihydrochloride salt by the procedureof example (2p)

Biological Activity

The MIC (μg/ml) of test compounds against various organisms wasdetermined including: S. epidermidis CL7, S. aureus WCUH29, S.pneumoniae 1629, S. pyogenes CN10, H. influenzae ATCC 49247, E. faecalis2, M. catarrhalis Ravasio, E. coli 7623. Examples 1, 5, 6, 7, 8, 11, 13have an MIC≦2 μg/ml versus all these organisms. Examples 4, 10, 12 havean MIC≦16 μg/ml versus all these organisms. Example 9 has an MIC≦16μg/ml versus some of these organisms.

1-16. (canceled)
 17. A compound of formula (I) or a pharmaceuticallyacceptable derivative thereof:

wherein: R^(A) is an optionally substituted bicyclic carbocyclic orheterocyclic ring system of structure:

containing 0-3 heteroatoms in each ring in which: at least one of rings(x) and (y) is aromatic; one of Z⁴ and Z⁵ is C or N and the other is C;Z³ is N, NR¹³, O, S(O)_(x), CO, CR¹ or CR¹R^(1a); Z¹ and Z² areindependently a 2 or 3 atom linker group each atom of which isindependently selected from N, NR¹³, O, S(O)_(x), CO, CR¹ and CR¹R^(1a);such that each ring is independently substituted with 0-3 groups R¹and/or R^(1a); one of Z¹, Z², Z³, Z⁴ and Z⁵ is N, one is CR^(1a) and theremainder are CH, or one of Z¹, Z², Z³, Z⁴ and Z⁵ is CR^(1a) and theremainder are CH; R¹ and R^(1a) are independently hydrogen; hydroxy;(C₁₋₆)alkoxy optionally substituted by (C₁₋₆)alkoxy, amino, piperidyl,guanidino or amidino any of which is optionally N-substituted by one ortwo (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups, CONH₂, hydroxy,(C₁₋₆)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy,acylthio, acyloxy or (C₁₋₆)alkylsulphonyloxy;(C₁₋₆)alkoxy-substituted(C₁₋₆)alkyl; hydroxy (C₁₋₆)alkyl; halogen;(C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluoromethyl; trifluoromethoxy; cyano;carboxy; nitro; azido; acyl; acyloxy; acylthio; (C₁₋₆)alkylsulphonyl;(C₁₋₆)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino,piperidyl, guanidino or amidino group optionally N-substituted by one ortwo (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups, or when Z³ and theadjacent atom are CR¹ and CR^(1a), R¹ and R^(1a) may together represent(C₁₋₂)alkylenedioxy; provided that R¹ and R^(1a), on the same carbonatom are not both optionally substituted hydroxy or amino; provided that(i) when R^(A) is optionally substituted quinolin-4-yl: it isunsubstituted in the 6-position; or it is substituted by at least onehydroxy (C₁₋₆)alkyl, cyano or carboxy group at the 2-, 5-, 6-, 7- or8-position; or it is substituted by at least one trifluoromethoxy group;or R¹ and R^(1a) together represent (C₁₋₂)alkylenedioxy; (ii) when R^(A)is optionally substituted quinazolin-4-yl, cinnolin-4-yl,1,5-naphthyridin-4-yl, 1,7-naphthyridin-4-yl or 1,8-naphthyridin-4-yl:it is substituted by at least one hydroxy (C₁₋₆)alkyl, cyano or carboxygroup at the 2-, 5-, 6-, 7- or 8-position as available; or it issubstituted by at least one trifluoromethoxy group; or R¹ and R^(1a)together represent (C₁₋₂)alkylenedioxy; R² is hydrogen, or (C₁₋₄)alkylor (C₂₋₄)alkenyl optionally substituted with 1 to 3 groups selectedfrom: amino optionally substituted by one or two (C₁₋₄)alkyl groups;carboxy; (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; aminocarbonyl whereinthe amino group is optionally substituted by hydroxy, (C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, aminocarbonyl(C₁₋₄)alkyl, (C₂₋₄)alkenyl,(C₁₋₄)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₄)alkenylsulphonyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl or(C₂₋₄)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionallysubstituted by R¹⁰; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl;2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl;1,2,4-triazol-5-yl optionally substituted by R¹⁰;5-oxo-1,2,4-oxadiazol-3-yl; halogen; (C₁₋₄)alkylthio; trifluoromethyl;hydroxy optionally substituted by (C₁₋₄)alkyl, (C₂₋₄)alkenyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl; oxo; (C₁₋₄)alkylsulphonyl;(C₂₋₄)alkenylsulphonyl; or (C₁₋₄)aminosulphonyl wherein the amino groupis optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl; R³ ishydrogen; or R³ is in the 2-, 3- or 4-position and is: trifluoromethyl;carboxy; (C₁₋₆)alkoxycarbonyl; (C₂₋₆)alkenyloxycarbonyl; aminocarbonylwherein the amino group is optionally substituted by hydroxy,(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl,(C₂₋₆)alkenylsulphonyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyl and optionally furthersubstituted by (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkylor (C₂₋₆)alkenyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionallysubstituted by R¹⁰; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl;2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl;1,2,4-triazol-5-yl optionally substituted by R¹⁰; or5-oxo-1,2,4-oxadiazol-3-yl; or (C₁₋₄)alkyl or ethenyl optionallysubstituted with any of the substituents listed above for R³ and/or 0 to2 groups R¹² independently selected from: halogen; (C₁₋₆)alkylthio;trifluoromethyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; (C₂₋₆)alkenylcarbonyl; hydroxy optionallysubstituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,(C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylcarbonyl or(C₂₋₆)alkenylcarbonyl; amino optionally mono- or disubstituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl,(C₂₋₆)alkenylsulphonyl or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; aminocarbonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; oxo;(C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl or(C₂₋₆)alkenyl; or R³ is in the 2-position and is oxo; or R³ is in the3-position and is fluorine, amino optionally substituted by a groupselected from hydroxy, (C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl,(C₂₋₆)alkenylsulphonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenylcarbonyl,(C₁₋₆)alkoxycarbonyl, (C₂₋₆)alkenyloxycarbonyl, (C₁₋₆)alkyl and(C₂₋₆)alkenyl, wherein a (C₁₋₆)alkyl or (C₂₋₆)alkenyl moiety may beoptionally substituted with up to 2 groups R¹², or hydroxy optionallysubstituted as described above for R¹² hydroxy; in addition when R³ isdisubstituted with a hydroxy or amino containing substituent and carboxycontaining substituent these may together form a cyclic ester or amidelinkage, respectively; R⁴ is a group -U-R⁵ where U is selected from CO,SO₂ and CH₂ and R⁵ is an optionally substituted bicyclic carbocyclic orheterocyclic ring system (A):

containing up to four heteroatoms in each ring in which at least one ofrings (a)and (b) is aromatic; X¹ is C or N when part of an aromaticring, or CR¹⁴ when part of a non-aromatic ring; X² is N, NR¹³, O,S(O)_(x), CO or CR¹⁴ when part of an aromatic or non-aromatic ring ormay in addition be CR¹⁴R¹⁵ when part of a non aromatic ring; X³ and X⁵are independently N or C; Y¹ is a 0 to 4 atom linker group each atom ofwhich is independently selected from N, NR¹³, O, S(O)_(x), CO and CR¹⁴when part of an aromatic or non-aromatic ring or may additionally beCR¹⁴R¹⁵ when part of a non aromatic ring; Y² is a 2 to 6 atom linkergroup, each atom of Y² being independently selected from N, NR¹³, O,S(O)_(x), CO, CR¹⁴ when part of an aromatic or non-aromatic ring or mayadditionally be CR¹⁴R¹⁵ when part of a non aromatic ring; each of R¹⁴and R¹⁵ is independently selected from: H; (C₁₋₄)alkylthio; halo;carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl; (C₁₋₄)alkyl;(C₂₋₄)alkenyl; (C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally mono- or di-substituted by(C₁₋₄)alkyl or (C₂₋₄)alkenyl; aryl; aryl(C₁₋₄)alkyl; aryl(C₁₋₄)alkoxy orR¹⁴ and R¹⁵ may together represent oxo; each R¹³ is independently H;trifluoromethyl; (C₁₋₄)alkyl optionally substituted by hydroxy,(C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halo or trifluoromethyl; (C₂₋₄)alkenyl;aryl; aryl (C₁₋₄)alkyl; arylcarbonyl; heteroarylcarbonyl;(C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; formyl; (C₁₋₆)alkylsulphonyl;or aminocarbonyl wherein the amino group is optionally substituted by(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or (C₂₋₄)alkenyl and optionallyfurther substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl; each x isindependently 0, 1 or 2 n is 0 and AB is NR¹¹CO, CO—CR⁸R⁹, CR⁶R⁷—CO,NHR¹¹—SO₂, CR⁶R⁷—SO₂ or CR⁶R⁷—CR⁸R⁹, provided that R⁸ and R⁹ are notoptionally substituted hydroxy or amino and R⁶ and R⁸ do not represent abond: or n is 1 and AB is NR¹¹CO, CO—CR⁸R⁹, CR⁶R⁷—CO, NR¹¹SO₂, CONR¹¹,CR⁶R⁷—CR⁸R⁹, O—CR⁸R⁹ or NR¹¹—CR⁸R⁹; provided that R⁶ and R⁷, and R⁸ andR⁹ are not both optionally substituted hydroxy or amino; and wherein:each of R⁶, R⁷, R⁸ and R⁹ is independently selected from: H;(C₁₋₆)alkoxy; (C₁₋₆)alkylthio; halo; trifluoromethyl; azido;(C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; (C₂₋₆)alkenylcarbonyl; hydroxy, amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or(C₁₋₆)aminosulphonyl wherein the amino group is optionally substitutedby (C₁₋₆)alkyl or (C₂₋₆)alkenyl; or R⁶ and R⁸ together represent a bondand R⁷ and R⁹ are as above defined; R¹⁰ is selected from (C₁₋₄)alkyl;(C₂₋₄)alkenyl and aryl any of which may be optionally substituted by agroup R¹² as defined above; carboxy; aminocarbonyl wherein the aminogroup is optionally substituted by hydroxy, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkylor (C₂₋₆)alkenyl; and R¹¹ is hydrogen; trifluoromethyl, (C₁₋₆)alkyl;(C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl or (C₂₋₆)alkenyl and optionallyfurther substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; or where one of R³and R⁶, R⁷, R⁸ or R⁹ contains a carboxy group and the other contains ahydroxy or amino group they may together form a cyclic ester or amidelinkage.
 18. A compound according to claim 17 wherein R^(A) isoptionally substituted isoquinolin-5-yl, quinolin-8-yl,thieno[3,2-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl,quinoxalin-5-yl, isoquinolin-8-yl, [1,6]-naphthyridin-4-yl,1,2,3,4-tetrahydroquinoxalin-5-yl or 1,2-dihydroisoquinoline-8-yl.
 19. Acompound according to claim 17 wherein R¹ is H, methoxy, methyl, cyanoor halogen and R^(1a) is H.
 20. A compound according to claim 17 whereinR³ is hydrogen; optionally substituted hydroxy; optionally substitutedamino; halogen; (C₁₋₄)alkoxycarbonyl; CONH₂; 1-hydroxyalkyl; CH₂CO₂H;CH₂CONH₂; —CONHCH₂CONH₂; 1,2-dihydroxyalkyl; CH₂CN;2-oxo-oxazolidin-5-yl; or 2-oxo-oxazolidin-5-yl(C₁₋₄alkyl).
 21. Acompound according to claim 17 wherein n is 0 and A and B are both CH₂,A is CHOH and B is CH₂ or A is NH and B is CO.
 22. A compound accordingto claim 17 wherein -U- is —CH₂—.
 23. A compound according to claim 17wherein the heterocyclic ring (A) having 8-11 ring atoms including 2-4heteroatoms of which at least one is N or NR¹³ in which Y² contains 2-3heteroatoms, one of which is S and 1-2 are N, with one N bonded to X³ orthe heterocyclic ring (A) has ring (a) aromatic selected from optionallysubstituted benzo and pyrido and ring (b) non aromatic and Y² has 3-5atoms, including a heteroatom bonded to X⁵ selected from O, S or NR¹³,where R¹³ is other than hydrogen, and NHCO bonded via N to X³, or Obonded to X³.
 24. A compound according to claim 17 wherein R⁵ isselected from: 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl.
 25. A compound according toclaim 17 selected from:4-(2-{4-[(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-piperidin-1-yl}-ethyl)-quinoline-6-carbonitrile6-({(3R,4S)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one6-({(3S,4R)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one6-({(3R,4R)-3-Hydroxy-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one6-({(3S,4S)-3-Hydroxy-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one6-({(3R,4S)-1-[2-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-3-fluoro-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one6-{[(1-{(2R/S)-2-hydroxy-2-[3-(methyloxy)-5-quinoxalinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one(1R/S)-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-(methyloxy)-5-quinoxalinyl]ethanol{1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine6-{[(1-(2-hydroxy-2-[2-(methyloxy)-8-quinolinyl]ethyl)-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one6-[({1-[2-(4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile(isomer E2)4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile(isomer E2)4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile(E1 isomer)4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile(E1 isomer) or a pharmaceutically acceptable derivative thereof.
 26. Amethod of treatment of bacterial infections in mammals, particularly inman, which method comprises the administration to a mammal in need ofsuch treatment an effective amount of a compound according to claim 17.27. A pharmaceutical composition comprising a compound according toclaim 17, and a pharmaceutically acceptable carrier.
 28. A process forpreparing a compound of formula (I) according to claim 17, or apharmaceutically acceptable derivative thereof, which process comprisesreacting a compound of formula (IV) with a compound of formula (V):

wherein n is as defined in formula (I); Z^(1′), Z^(2′), Z^(3′), R^(1′),and R^(3′) are Z¹, Z², Z³, R¹, and R³ as defined in formula (I) orgroups convertible thereto; Z⁴ and Z⁵ are as defined in formula (I); Q¹is NR^(2′)R^(4′) or a group convertible thereto wherein R^(2′) andR^(4′) are R² and R⁴ as defined in formula (I) or groups convertiblethereto and Q² is H or R^(3′) or Q¹ and Q² together form an optionallyprotected oxo group; (i) X is A′-COW, Y is H and n is 0; (ii) X isCR⁶═CR⁸R⁹, Y is H and n is 0; (iii) X is oxirane, Y is H and n is 0;(iv) X is N═C═O and Y is H and n is 0; (v) one of X and Y is CO₂R^(y)and the other is CH₂CO₂R^(x); (vi) X is CHR⁶R⁷ and Y is C(═O)R⁹; (vii) Xis CR⁷═PR^(z) ₃ and Y is C(═O)R⁹ and n=1; (viii) X is C(═O)R⁷ and Y isCR⁹═PR^(z) ₃ and n=1; (ix) Y is COW and X is NHR^(11′), NCO or NR^(11′)COW and n=0 or 1 or when n=1 X is COW and Y is NHR^(11′), NCO orNR^(11′) COW; (x) X is NHR^(11′) and Y is C(═O)R⁸ and n=1; (xi) X isNHR^(11′) and Y is CR⁸R⁹W and n=1; (xii) X is NR^(11′)COCH₂W orNR^(11′)SO₂CH₂W and Y is H and n=0; (xiii) X is CR⁶R⁷SO₂W and Y is H andn=0; (xiv) X is W or OH and Y is CH₂OH and n is 1; (xv) X is NHR^(11′)and Y is SO₂W or X is NR^(11′)SO₂W and Y is H, and n is 0; (xvi) X is Wand Y is CONHR^(11′); (xvii) X is —CH═CH₂ and Y is H and n=0; in which Wis a leaving group, e.g. halo, methanesulphonyloxy,trifluoromethanesulphonyloxy or imidazolyl; R^(x) and R^(y) are(C₁₋₆)alkyl; R^(z) is aryl or (C₁₋₆)alkyl; A′ and NR^(11′) are A andNR¹¹ as defined in formula (I), or groups convertible thereto; andoxirane is:

wherein R⁶, R⁸ and R⁹ are as defined in formula (I); and thereafteroptionally or as necessary converting Q¹ and Q² to NR^(2′)R^(4′);converting A′, Z^(1′), Z^(2′), Z^(3′), R^(1′), R^(2′), R^(3′), R^(4′)and NR^(11′); to A, Z¹, Z², Z³, R¹, R², R³, R⁴ and NR¹¹; converting A-Bto other A-B, interconverting R¹, R², R³ and/or R⁴, and/or forming apharmaceutically acceptable derivative thereof.